User:Christina Evans/Sandbox 1 - Revision history

Christina Evans at 09:02, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 09:02:03 GMT

←Older revision		Revision as of 09:02, 7 December 2012
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	2. [[Major Histocompatibility Complex]]		2. [[Major Histocompatibility Complex]]
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-	3. Greene, J. M., Wiseman, R. W., Lank, S. M., Bimber, B. N., Karl, J. A., Burwitz, B. J., Lhost, J. J., Hawkins, O. E., Kunstman, K. J., Broman, K. W., Wolinsky, S. M., Hildebrand, W. H., O’Connor, D. H. (2011). Differential MHC class I expression in distinct leukocyte subsets. BMC Immunology, 12(39) 1-17.
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-	3. Ho, M. (2008). The history of cytomegalovirus and its diseases. Medical Microbiology and Immunology, 197(2) 65-73

Christina Evans at 08:51, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 08:51:53 GMT

(Difference between revisions)

Christina Evans at 07:35, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 07:35:43 GMT

←Older revision		Revision as of 07:35, 7 December 2012
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-	[[Image:HCMV_Model_Poster.jpg\|thumb\|left\|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]In some cases, a virus is able to disrupt the function of the MHC-I, which makes the virus undetectable by the immune system. Human cytomegalovirus (HCMV) is a β herpesvirus that can cause serious illness in children and immunodeficient patients, and it is able to establish latency within a host cell by disrupting the function of MHC-I. This poses a problem during tissue transplants, because it has been found that a significant number of organ transplants result in patients infected with HCMV, due to the virus’s ability to establish latency. HCMV produces a glycoprotein, called unique short 2 (US2), which binds to MHC-I inhibiting expression of MHC-I and preventing CTL recognition and destruction of HCMV-infected cells. When US2 binds to MHC-I in the ER, the molecules are sent to the cytoplasm for degradation by the proteasome. US2 is produced by a region of the HCMV genome that encodes eight short glycoproteins of a unique sequence that help the virus evade the host’s immune system. US2 is able to form a tight bond with MHC-I because of its structure. In order to determine the structure scientists used X-ray crystallography, an experimental method that crystallizes a protein so an X-ray can be diffracted off the surface, thereby revealing the structure. X-ray crystallography has revealed that US2 contains an immunoglobulin fold (Ig fold), which appears to play a role in evading the immune system. An Ig fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The flat surface of the beta sheets in US2 provides a good surface to bind extensively with one of the beta sheets on HLA. Research has determined that one residue in particular (R181) on this binding surface is responsible for the dislocation of MHC to the cytoplasm. Pulse chase analysis, a technique used to see cellular processes that take place over time, was used in an experiment performed by Gewurz et. al. to see if a specific residue is responsible for the dislocation of MHC. During the experiment the researchers mutated certain residues on HLA that bond with residues on US2, the mutated HLA:US2 complex was then labeled, this is called the ‘pulse,’ and then went through its cellular processes. Mutations at residues R131E, R157E, & R181E were tested for dislocation immediately following the pulse (0 minutes) and 30 minutes later. After 30 minutes, US2 dislocation is seen with R131E and R157E, but not with R181E. This result indicates R181 is an important binding site for US2-mediated dislocation. 2 Presently, research has not been able to determine exactly why this residue causes MHC-I dislocation to the cytoplasm, or how to prevent the dislocation, so there is no proven way to prevent HCMV establish latency within the cell. Hopefully in the near future research will reveal a way to disrupt the function of US2, so HCMV will no longer be unknowingly passed to patients receiving tissue donations.	+	[[Image:HCMV_Model_Poster.jpg\|thumb\|left\|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]In some cases, a virus is able to disrupt the function of the MHC-I, which makes the virus undetectable by the immune system. Human cytomegalovirus (HCMV) is a β herpesvirus that can cause serious illness in children and immunodeficient patients, and it is able to establish latency within a host cell by disrupting the function of MHC-I. This poses a problem during tissue transplants, because it has been found that a significant number of organ transplants result in patients infected with HCMV, due to the virus’s ability to establish latency. HCMV produces a glycoprotein, called unique short 2 (<scene name='User:Christina_Evans/Sandbox_1/1im3_us2/1'>US2</scene>), which binds to MHC-I inhibiting expression of MHC-I and preventing CTL recognition and destruction of HCMV-infected cells. When US2 binds to MHC-I in the ER, the molecules are sent to the cytoplasm for degradation by the proteasome. US2 is produced by a region of the HCMV genome that encodes eight short glycoproteins of a unique sequence that help the virus evade the host’s immune system. US2 is able to form a tight bond with MHC-I because of its structure. In order to determine the structure scientists used X-ray crystallography, an experimental method that crystallizes a protein so an X-ray can be diffracted off the surface, thereby revealing the structure. X-ray crystallography has revealed that US2 contains an immunoglobulin fold (<scene name='User:Christina_Evans/Sandbox_1/1im3_us2_cartoon/2/1'>Ig fold</scene>), which appears to play a role in evading the immune system. An Ig fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The flat surface of the beta sheets in US2 provides a good surface to <scene name='User:Christina_Evans/Sandbox_1/1im3_hla_us2/1'>bind extensively</scene> with one of the beta sheets on HLA. Research has determined that one residue in particular (<scene name='User:Christina_Evans/Sandbox_1/1im3_hla_181/1'>R181</scene>) on this binding surface is responsible for the dislocation of MHC to the cytoplasm. Pulse chase analysis, a technique used to see cellular processes that take place over time, was used in an experiment performed by Gewurz et. al. to see if a specific residue is responsible for the dislocation of MHC. During the experiment the researchers mutated certain residues on HLA that bond with residues on US2, the mutated HLA:US2 complex was then labeled, this is called the ‘pulse,’ and then went through its cellular processes. Mutations at residues R131E, R157E, & R181E were tested for dislocation immediately following the pulse (0 minutes) and 30 minutes later. After 30 minutes, US2 dislocation is seen with R131E and R157E, but not with R181E. This result indicates R181 is an important binding site for US2-mediated dislocation. Presently, research has not been able to determine exactly why this residue causes MHC-I dislocation to the cytoplasm, or how to prevent the dislocation, so there is no proven way to prevent HCMV establish latency within the cell. Hopefully in the near future research will reveal a way to disrupt the function of US2, so HCMV will no longer be unknowingly passed to patients receiving tissue donations.

Christina Evans at 06:37, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 06:37:13 GMT

←Older revision		Revision as of 06:37, 7 December 2012
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-	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_helix/1'>α-helical</scene> (shown in <font color='indigo'>indigo</font>) regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_sheet/1'>β strands</scene> (shown in <font color='blue'>blue</font>). β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. The peptide is held in the peptide binding groove by <scene name='User:Christina_Evans/Sandbox_1/1im3_anchor_residues/1'>anchor residues</scene> (shown in <font color='cyan'>cyan</font>) , which are amino acids located at the terminal ends of the peptide. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.	+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_helix/1'>α-helical</scene> (shown in <font color='indigo'>indigo</font>) regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_sheet/1'>β strands</scene> (shown in <font color='blue'>blue</font>). β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. The peptide is held in the <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove/1'>peptide binding groove</scene> by <scene name='User:Christina_Evans/Sandbox_1/1im3_anchor_residues/1'>anchor residues</scene> (shown in <font color='cyan'>cyan</font>) , which are amino acids located at the terminal ends of the peptide. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.

	Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.		Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.

Christina Evans at 06:26, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 06:26:57 GMT

←Older revision		Revision as of 06:26, 7 December 2012
Line 17:		Line 17:


-	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_helix/1'>α-helical</scene> (shown in <font color='indigo'>indigo</font>) regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_sheet/1'>β strands</scene> (shown in <font color='blue'>blue</font>). β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. ~~Amino~~ acids located at the terminal ends of the peptide~~, hold the peptides in the MHC-1 binding groove and are called anchor residues~~. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.	+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_helix/1'>α-helical</scene> (shown in <font color='indigo'>indigo</font>) regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_sheet/1'>β strands</scene> (shown in <font color='blue'>blue</font>). β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. The peptide is held in the peptide binding groove by <scene name='User:Christina_Evans/Sandbox_1/1im3_anchor_residues/1'>anchor residues</scene> (shown in <font color='cyan'>cyan</font>) , which are amino acids located at the terminal ends of the peptide. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.

	Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.		Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.
Line 26:		Line 26:
	[[Image:Viral_presentation.jpg\|thumb\|Proper viral antigen presentation on MHC-I. TAP (transporter associated with antigen presentation). Adapted from Kochar, P. (2012, January). Csa. Retrieved from http://www.csa.com/discoveryguides/cancer/review.php]]		[[Image:Viral_presentation.jpg\|thumb\|Proper viral antigen presentation on MHC-I. TAP (transporter associated with antigen presentation). Adapted from Kochar, P. (2012, January). Csa. Retrieved from http://www.csa.com/discoveryguides/cancer/review.php]]

-	MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, β2M binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a <scene name='User:Christina_Evans/Sandbox_1/1im3_peptide/1'>peptide</scene> (shown in <font color='deeppink'>pink</font>) is loaded into the binding cleft~~. The peptide sits in a cleft formed by two α1 and α2 domains. The binding cleft is composed of two alpha helices that form walls and a β sheet that makes up the floor~~. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.	+	MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, β2M binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a <scene name='User:Christina_Evans/Sandbox_1/1im3_peptide/1'>peptide</scene> (shown in <font color='deeppink'>pink</font>) is loaded into the binding cleft. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable <scene name='User:Christina_Evans/Sandbox_1/1im3_mhc-us2/1'>MHC-I:peptide complex</scene> is targeted to the surface of the cell via the Golgi apparatus.

Christina Evans at 06:11, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 06:11:20 GMT

←Older revision		Revision as of 06:11, 7 December 2012
Line 17:		Line 17:


-	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/~~1im3_alpha~~/1'>α-helical</scene> regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/~~1im3_beta~~/1'>β strands</scene>. β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. Amino acids located at the terminal ends of the peptide, hold the peptides in the MHC-1 binding groove and are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.	+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_helix/1'>α-helical</scene> (shown in <font color='indigo'>indigo</font>) regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_binding_groove_sheet/1'>β strands</scene> (shown in <font color='blue'>blue</font>). β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. Amino acids located at the terminal ends of the peptide, hold the peptides in the MHC-1 binding groove and are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.

	Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.		Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.
Line 26:		Line 26:
	[[Image:Viral_presentation.jpg\|thumb\|Proper viral antigen presentation on MHC-I. TAP (transporter associated with antigen presentation). Adapted from Kochar, P. (2012, January). Csa. Retrieved from http://www.csa.com/discoveryguides/cancer/review.php]]		[[Image:Viral_presentation.jpg\|thumb\|Proper viral antigen presentation on MHC-I. TAP (transporter associated with antigen presentation). Adapted from Kochar, P. (2012, January). Csa. Retrieved from http://www.csa.com/discoveryguides/cancer/review.php]]

-	MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, β2M binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a peptide is loaded into the binding cleft. The peptide sits in a cleft formed by two α1 and α2 domains. The binding cleft is composed of two alpha helices that form walls and a β sheet that makes up the floor. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.	+	MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, β2M binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a <scene name='User:Christina_Evans/Sandbox_1/1im3_peptide/1'>peptide</scene> (shown in <font color='deeppink'>pink</font>) is loaded into the binding cleft. The peptide sits in a cleft formed by two α1 and α2 domains. The binding cleft is composed of two alpha helices that form walls and a β sheet that makes up the floor. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.

Christina Evans at 05:22, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 05:22:48 GMT

←Older revision		Revision as of 05:22, 7 December 2012
Line 17:		Line 17:


-	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_alpha/1'>α-helical</scene> regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_beta/1'>β strands</scene>. β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a disulfide bond located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. Amino acids located at the terminal ends of the peptide, hold the peptides in the MHC-1 binding groove and are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.	+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_alpha/1'>α-helical</scene> regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_beta/1'>β strands</scene>. β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a <scene name='User:Christina_Evans/Sandbox_1/1im3_disulfide_bond_a/1'>disulfide bond</scene> located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. Amino acids located at the terminal ends of the peptide, hold the peptides in the MHC-1 binding groove and are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.

	Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.		Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.
Line 43:		Line 43:


-	[[Image:HCMV_Model_Poster.jpg\|thumb\|left\|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]In some cases, a virus is able to disrupt the function of the MHC-I, which makes the virus undetectable by the immune system. Human cytomegalovirus (HCMV) is a β herpesvirus that can cause serious illness in children and immunodeficient patients, and it is able to establish latency within a host cell by disrupting the function of MHC-I. This poses a problem during tissue transplants, because it has been found that a significant number of organ transplants result in patients infected with HCMV, due to the virus’s ability to establish latency. HCMV produces a glycoprotein, called unique short 2 (US2), which binds to MHC-I inhibiting expression of MHC-I and preventing CTL recognition and destruction of HCMV-infected cells. When US2 binds to MHC-I in the ER, the molecules are sent to the cytoplasm for degradation by the proteasome. US2 is produced by a region of the HCMV genome that encodes eight short glycoproteins of a unique sequence that help the virus evade the host’s immune system. US2 is able to form a tight bond with MHC-I because of its structure. In order to determine the structure scientists used X-ray crystallography, an experimental method that crystallizes a protein so an X-ray can be diffracted off the surface, thereby revealing the structure. X-ray crystallography has revealed that US2 contains an immunoglobulin fold (Ig fold), which appears to play a role in evading the immune system. An Ig fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The flat surface of the beta sheets in US2 provides a good surface to bind extensively with one of the beta sheets on HLA. Research has determined that one residue in particular on this binding surface is responsible for the dislocation of MHC to the cytoplasm. Pulse chase analysis, a technique used to see cellular processes that take place over time, was used in an experiment performed by Gewurz et. al. to see if a specific residue is responsible for the dislocation of MHC. During the experiment the researchers mutated certain residues on HLA that bond with residues on US2, the mutated HLA:US2 complex was then labeled, this is called the ‘pulse,’ and then went through its cellular processes. Mutations at residues R131E, R157E, & R181E were tested for dislocation immediately following the pulse (0 minutes) and 30 minutes later. After 30 minutes, US2 dislocation is seen with R131E and R157E, but not with R181E. This result indicates R181 is an important binding site for US2-mediated dislocation. 2 Presently, research has not been able to determine exactly why this residue causes MHC-I dislocation to the cytoplasm, or how to prevent the dislocation, so there is no proven way to prevent HCMV establish latency within the cell. Hopefully in the near future research will reveal a way to disrupt the function of US2, so HCMV will no longer be unknowingly passed to patients receiving tissue donations.	+	[[Image:HCMV_Model_Poster.jpg\|thumb\|left\|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]In some cases, a virus is able to disrupt the function of the MHC-I, which makes the virus undetectable by the immune system. Human cytomegalovirus (HCMV) is a β herpesvirus that can cause serious illness in children and immunodeficient patients, and it is able to establish latency within a host cell by disrupting the function of MHC-I. This poses a problem during tissue transplants, because it has been found that a significant number of organ transplants result in patients infected with HCMV, due to the virus’s ability to establish latency. HCMV produces a glycoprotein, called unique short 2 (US2), which binds to MHC-I inhibiting expression of MHC-I and preventing CTL recognition and destruction of HCMV-infected cells. When US2 binds to MHC-I in the ER, the molecules are sent to the cytoplasm for degradation by the proteasome. US2 is produced by a region of the HCMV genome that encodes eight short glycoproteins of a unique sequence that help the virus evade the host’s immune system. US2 is able to form a tight bond with MHC-I because of its structure. In order to determine the structure scientists used X-ray crystallography, an experimental method that crystallizes a protein so an X-ray can be diffracted off the surface, thereby revealing the structure. X-ray crystallography has revealed that US2 contains an immunoglobulin fold (Ig fold), which appears to play a role in evading the immune system. An Ig fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The flat surface of the beta sheets in US2 provides a good surface to bind extensively with one of the beta sheets on HLA. Research has determined that one residue in particular (R181) on this binding surface is responsible for the dislocation of MHC to the cytoplasm. Pulse chase analysis, a technique used to see cellular processes that take place over time, was used in an experiment performed by Gewurz et. al. to see if a specific residue is responsible for the dislocation of MHC. During the experiment the researchers mutated certain residues on HLA that bond with residues on US2, the mutated HLA:US2 complex was then labeled, this is called the ‘pulse,’ and then went through its cellular processes. Mutations at residues R131E, R157E, & R181E were tested for dislocation immediately following the pulse (0 minutes) and 30 minutes later. After 30 minutes, US2 dislocation is seen with R131E and R157E, but not with R181E. This result indicates R181 is an important binding site for US2-mediated dislocation. 2 Presently, research has not been able to determine exactly why this residue causes MHC-I dislocation to the cytoplasm, or how to prevent the dislocation, so there is no proven way to prevent HCMV establish latency within the cell. Hopefully in the near future research will reveal a way to disrupt the function of US2, so HCMV will no longer be unknowingly passed to patients receiving tissue donations.

Christina Evans at 05:01, 7 December 2012

Christina Evans — Fri, 07 Dec 2012 05:01:17 GMT

←Older revision		Revision as of 05:01, 7 December 2012
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-	<Structure load='1im3' size='500' frame='true' align='right' caption='1IM3' scene='User:Christina_Evans/Sandbox_1/~~1im3_correct~~/2'/>	+	<Structure load='1im3' size='500' frame='true' align='right' caption='1IM3' scene='User:Christina_Evans/Sandbox_1/1im3_practice_3/3'/>


	'''Description of Class I MHC'''		'''Description of Class I MHC'''

-	Class I major histocompatibility molecules <scene name='User:Christina_Evans/Sandbox_1/1im3_correct/2'>(MHC-I)</scene> are cell surface proteins that signal the presence of intracellular pathogens, such as viruses, to the host’s immune system. When viruses invade a host cell, they use the cell’s machinery to reproduce their nucleic acid and synthesize their proteins. Viral proteins, like cellular proteins, become targets for degradation and recycling, generating small portions of the viral proteins called peptides. Viral peptides of the right size can fit into the binding cleft of MHC-1 molecules, which are then displayed on the surface of the viral-infected cell. Cytotoxic T Lymphocytes (CTL), have receptors for foreign (viral) peptides complexed to MHC-1. When a CTL binds to a viral peptide-MHC-1 complex, the CTL secretes substances that lead to lysis and death of the infected cell, eventually clearing the infection. Thus, MHC-1 molecules function as an important warning system for the presence of intracellular infections. Viruses that develop a way to prevent expression of MHC-1 on the cell surface have a better chance of survival in the host.	+	Class I major histocompatibility molecules <scene name='User:Christina_Evans/Sandbox_1/1im3_correct/2'>(MHC-I)</scene> are cell surface proteins that signal the presence of intracellular pathogens, such as viruses, to the host’s immune system. When viruses invade a host cell, they use the cell’s machinery to reproduce their nucleic acid and synthesize their proteins. Viral proteins, like cellular proteins, become targets for degradation and recycling, generating small portions of the viral proteins called peptides. Viral peptides of the right size can fit into the binding cleft of MHC-1 molecules, which are then displayed on the surface of the viral-infected cell. Cytotoxic T Lymphocytes (CTL) have receptors for foreign (viral) peptides complexed to MHC-1. When a CTL binds to a viral peptide-MHC-1 complex, the CTL secretes substances that lead to lysis and death of the infected cell, eventually clearing the infection. Thus, MHC-1 molecules function as an important warning system for the presence of intracellular infections. Viruses that develop a way to prevent expression of MHC-1 on the cell surface have a better chance of survival in the host.

	----		----
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	'''History of Class I MHC'''		'''History of Class I MHC'''

-	Major Histocompatibility proteins are encoded by a diverse set of genes that mediate transplant acceptance and rejection. MHC genes were discovered by scientists working on tissue rejection in inbred strains of mice and rabbits. Two scientists, E.E. Tyzzer and Clarence C. Little were interested in the genetic differences that control the immune response to transplanted tissues in mice. In 1916, they transplanted tumors from different strains of mice, and reported the acceptance and rejection of grafts between different strains. In a similar experiment, Bover found that tissues were accepted if the donor and recipient were identical twins. Bover concluded that rejection and acceptance of transplanted tissues is genetically controlled. In the 1940s, Peter Medawar ~~working~~ with rabbits confirmed that tissue graft rejection was triggered by an immune response. A few years later, George Snell ‘invented’ the congenic mouse strain. These mice were bred to be genetically identical, except at one locus. Snell called the locus that controlled tissue compatibility, histocompatibility ~~genes2~~. Later studies revealed several closely linked histocompatibility genes that are located on the same chromosome, and became known as the MHC gene complex. In humans, MHC proteins are also called the Human ~~Leucocyte~~ Antigen, or HLA, and can be used interchangeably.	+	Major Histocompatibility proteins are encoded by a diverse set of genes that mediate transplant acceptance and rejection. MHC genes were discovered by scientists working on tissue rejection in inbred strains of mice and rabbits. Two scientists, E.E. Tyzzer and Clarence C. Little were interested in the genetic differences that control the immune response to transplanted tissues in mice. In 1916, they transplanted tumors from different strains of mice, and reported the acceptance and rejection of grafts between different strains. In a similar experiment, Bover found that cancer tissues were accepted if the donor and recipient were identical twins. Bover concluded that rejection and acceptance of transplanted tissues is genetically controlled. In the 1940s, Peter Medawar, while performing a tissue compatibility experiment with rabbits, confirmed that tissue graft rejection was triggered by an immune response. Medawar would perform skin grafts on rabbits to determine if the tissues were compatible, if the tissue was rejected he would transplant the same tissue again on the same recipient, and it was found that the tissue rejection occurred twice as fast. This indicated that the rejection was caused by an adaptive immune response, because the immune system was quicker to respond to the repeated procedure. A few years later, George Snell ‘invented’ the congenic mouse strain. These mice were bred to be genetically identical, except at one locus, which is what made them congenic. During each new generation of mice, Snell would perform a skin allograft on them to determine if they would accept or reject the tissue. Snell would then continue to inbreed the mice that rejected the skin graft, but were identical in every other aspect. After many inbreeds, Snell was able to determine the location of tissue compatibility on the chromosome. Snell called the locus that controlled tissue compatibility, histocompatibility genes. Later studies revealed several closely linked histocompatibility genes that are located on the same chromosome, and became known as the MHC gene complex. In humans, MHC proteins are also called the Human Leukocyte Antigen, or HLA, and can be used interchangeably. HLA was first discovered by Gorer in his work with blood antigens and tissue grafts. Gorer observed that recipients who received a tumor transplant from a donor that had different blood antigens, the tissue would be rejected. The genetic differences in the antigens present on blood cells would cause an immune reaction during a tissue donation, much like what occurs in mice when they have different MHC genes. The discovery of the HLA/MHC locus has prompted many studies in the field of tissue grafts, to help lower the risk of a patient receiving an incompatible tissue donation.


-	'''Stucture of Class I MHC'''	+	'''Stucture of Class I MHC'''
		+
		+
		+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> chain and beta-2 microglobulin (<scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_alpha/1'>α-helical</scene> regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_beta/1'>β strands</scene>. β2M associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also stabilized by a disulfide bond located within the β sheets. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and host cell peptides can be bound. Amino acids located at the terminal ends of the peptide, hold the peptides in the MHC-1 binding groove and are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.
		+
		+	Each person has their own repertoire of MHC-I molecules, because they are highly polygenic and polymorphic. There are many genetic variants of MHC-I in the human population, this makes the MHC-I protein polymorphic. There are also many genes that code for MHC-I molecules, which makes MHC-I polygenic. We inherit our MHC-I molecules from our parents, both the mother and father contribute three α chains, so each person has six α chains total. The likelihood of an individual to inherit identical copies of their parent’s α chains is very low, because of the extremely varied, or polymorphic, nature of the alleles that control the expression of the α chain on MHC-I. This increased chance of a person being heterozygous for each MHC-I molecule is advantageous, because this ensures that a person will have plenty of different MHC-I molecules to protect them against many different viruses.

-	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> and Beta-2 microglobulin <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_alpha/1'>α-helical</scene> regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_beta/1'>β strands</scene> . β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.


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	[[Image:Viral_presentation.jpg\|thumb\|Proper viral antigen presentation on MHC-I. TAP (transporter associated with antigen presentation). Adapted from Kochar, P. (2012, January). Csa. Retrieved from http://www.csa.com/discoveryguides/cancer/review.php]]		[[Image:Viral_presentation.jpg\|thumb\|Proper viral antigen presentation on MHC-I. TAP (transporter associated with antigen presentation). Adapted from Kochar, P. (2012, January). Csa. Retrieved from http://www.csa.com/discoveryguides/cancer/review.php]]

-	MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, ~~2M~~ binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a peptide is loaded into the binding cleft. The peptide sits in a cleft formed by two α1 and 2 domains. The binding cleft is composed of two alpha helices that form walls and a β sheet that makes up the floor. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.	+	MHC-1 molecules are synthesized in ribosomes anchored in the membrane of the endoplasmic reticulum (ER). In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. When Calnexin is released, β2M binds to the α chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a peptide is loaded into the binding cleft. The peptide sits in a cleft formed by two α1 and α2 domains. The binding cleft is composed of two alpha helices that form walls and a β sheet that makes up the floor. Once the peptide is bound to MHC-I, Transporters Associated with Antigen Processing (TAP), tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.


Line 28:		Line 32:


-	When a virus injects its nucleic acid into a host cell, it uses the cell’s machinery to replicate its genome and synthesize its proteins. Because the viral proteins are being made within the host cell, the viral proteins can undergo recycling just like host cell proteins. Misfolded proteins are marked for destruction in the cytosol by the addition of a small molecule called, ubiquitin. Once ubiquitin is attached, the protein is sent to the proteasome. Proteosomes are large cylindrical structures with many proteolytic enzymes. In the presence of a virus, the proteasome cleaves proteins into peptides 8-10 residues long with the appropriate anchor residues ensuring a stable fit into the peptide binding cleft of the MHC-I molecule. The peptides are transported from the cytosol to the lumen of the Endoplasmic Reticulum (ER) via ER membrane proteins ~~called Transporters Associated with Antigen Processing (~~TAP).	+	When a virus injects its nucleic acid into a host cell, it uses the cell’s machinery to replicate its genome and synthesize its proteins. Because the viral proteins are being made within the host cell, the viral proteins can undergo recycling just like host cell proteins. Misfolded proteins are marked for destruction in the cytosol by the addition of a small molecule called, ubiquitin. Once ubiquitin is attached, the protein is sent to the proteasome. Proteosomes are large cylindrical structures with many proteolytic enzymes. In the presence of a virus, the proteasome cleaves proteins into peptides 8-10 residues long with the appropriate anchor residues ensuring a stable fit into the peptide binding cleft of the MHC-I molecule. The peptides are transported from the cytosol to the lumen of the Endoplasmic Reticulum (ER) via ER membrane proteins, TAP.


	'''Function of MHC-I'''		'''Function of MHC-I'''

-	The function of MHC-I is to alert the immune system that something is wrong with the host ~~cell5~~. When an infected cell displays a viral peptide via MHC-I, Cytotoxic T Lymphocytes (CTLs) are attracted to it. CTLs use their T Cell Receptor (TCR) to bind to the viral peptide that is on display. Each CTL has its own TCR, which is able to detect its own foreign peptide. This variability among TCRs is made possible when the genes of a T cell shuffle to form its own, unique TCR. This ensures that many different peptides can be recognized by CTLs, so our body is thoroughly protected. TCRs that bind to self-peptides that are displayed on MHC-I are destroyed before they are allowed to travel around the ~~body2~~. Once a TCR finds an MHC-I displaying its complementary peptide, the CTL binds strongly to the peptide. The interaction is strengthened with the help of a glycoprotein called, Cluster of Differentiation 8 (CD8) that is found on the surface of the CTL. When the TCR binds the peptide, CD8 binds to the MHC-I complex, forming a stronger bond between the CTL and the host ~~cell1~~. After a strong bond has been made, the CTL is activated by signaling pathways and it starts to release perforin, a protein that makes pores in the surface of the infected host cell. The pores help granzymes, proteases that are released by the CTL, enter the infected host cell and attack the cell from the inside. CTLs also release cytokines, proteins that are secreted by one cell and cause an effect on another, that help the CTLs multiply, and activates them so they will start attacking other infected host ~~cells3~~. None of this can occur, however, if MHC-I is not able to perform its function, and display viral peptides on the host cells surface.	+	The function of MHC-I is to alert the immune system that something is wrong with the host cell. When an infected cell displays a viral peptide via MHC-I, Cytotoxic T Lymphocytes (CTLs) are attracted to it. CTLs use their T Cell Receptor (TCR) to bind to the viral peptide that is on display. Each CTL has its own TCR, which is able to detect its own foreign peptide. This variability among TCRs is made possible when the genes of a T cell shuffle to form its own, unique TCR. This ensures that many different peptides can be recognized by CTLs, so our body is thoroughly protected. TCRs that bind to self-peptides that are displayed on MHC-I are destroyed before they are allowed to travel around the body. Once a TCR finds an MHC-I displaying its complementary peptide, the CTL binds strongly to the peptide. The interaction is strengthened with the help of a glycoprotein called, Cluster of Differentiation 8 (CD8) that is found on the surface of the CTL. When the TCR binds the peptide, CD8 binds to the MHC-I complex, forming a stronger bond between the CTL and the host cell. After a strong bond has been made, the CTL is activated by signaling pathways and it starts to release perforin, a protein that makes pores in the surface of the infected host cell. The pores help granzymes, proteases that are released by the CTL, enter the infected host cell and attack the cell from the inside. CTLs also release cytokines, proteins that are secreted by one cell and cause an effect on another, that help the CTLs multiply, and activates them so they will start attacking other infected host cells. None of this can occur, however, if MHC-I is not able to perform its function, and display viral peptides on the host cells surface.


Line 39:		Line 43:


-	[[Image:HCMV_Model_Poster.jpg\|thumb\|left\|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]~~When~~ a virus ~~such as HCMV binds~~ to MHC-I, the ~~whole mechanism for alerting~~ the immune system ~~is disrupted~~. HCMV ~~produces~~ a ~~glycoprotein called US2~~, ~~through research done~~ by ~~Gewurz et. al~~. it ~~was~~ found that US2 binds to ~~HLA~~-2, and ~~this somehow sends~~ MHC-I to the ~~cytosol~~ to ~~be destroyed, instead~~ of to the ~~cell~~ surface. ~~A structural study found~~ that US2 contains an immunoglobulin~~-like~~ fold (Ig~~-like~~ fold) ~~that~~ appears to play a role in evading the ~~host’s~~ immune system. An Ig-fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The ~~Ig-like fold~~ in US2 provides ~~an area for extensive binding~~ with ~~the HLA molecule along~~ one of the beta-sheets. ~~Using pulse chase analysis, it was~~ determined that one residue in particular ~~was~~ responsible for the dislocation of MHC-I to the cytoplasm. ~~It has been found~~ that a ~~significant number~~ of ~~organ transplants result in patients infected~~ with ~~HCMV~~, ~~because of~~ the ~~virus’s ability~~ to establish latency.	+	[[Image:HCMV_Model_Poster.jpg\|thumb\|left\|Poster that outlines effect of HCMV on MHC-I, written by Burke, et. al. Based on research performed by Gewurz, et. al.]]In some cases, a virus is able to disrupt the function of the MHC-I, which makes the virus undetectable by the immune system. Human cytomegalovirus (HCMV) is a β herpesvirus that can cause serious illness in children and immunodeficient patients, and it is able to establish latency within a host cell by disrupting the function of MHC-I. This poses a problem during tissue transplants, because it has been found that a significant number of organ transplants result in patients infected with HCMV, due to the virus’s ability to establish latency. HCMV produces a glycoprotein, called unique short 2 (US2), which binds to MHC-I inhibiting expression of MHC-I and preventing CTL recognition and destruction of HCMV-infected cells. When US2 binds to MHC-I in the ER, the molecules are sent to the cytoplasm for degradation by the proteasome. US2 is produced by a region of the HCMV genome that encodes eight short glycoproteins of a unique sequence that help the virus evade the host’s immune system. US2 is able to form a tight bond with MHC-I because of its structure. In order to determine the structure scientists used X-ray crystallography, an experimental method that crystallizes a protein so an X-ray can be diffracted off the surface, thereby revealing the structure. X-ray crystallography has revealed that US2 contains an immunoglobulin fold (Ig fold), which appears to play a role in evading the immune system. An Ig fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The flat surface of the beta sheets in US2 provides a good surface to bind extensively with one of the beta sheets on HLA. Research has determined that one residue in particular on this binding surface is responsible for the dislocation of MHC to the cytoplasm. Pulse chase analysis, a technique used to see cellular processes that take place over time, was used in an experiment performed by Gewurz et. al. to see if a specific residue is responsible for the dislocation of MHC. During the experiment the researchers mutated certain residues on HLA that bond with residues on US2, the mutated HLA:US2 complex was then labeled, this is called the ‘pulse,’ and then went through its cellular processes. Mutations at residues R131E, R157E, & R181E were tested for dislocation immediately following the pulse (0 minutes) and 30 minutes later. After 30 minutes, US2 dislocation is seen with R131E and R157E, but not with R181E. This result indicates R181 is an important binding site for US2-mediated dislocation. 2 Presently, research has not been able to determine exactly why this residue causes MHC-I dislocation to the cytoplasm, or how to prevent the dislocation, so there is no proven way to prevent HCMV establish latency within the cell. Hopefully in the near future research will reveal a way to disrupt the function of US2, so HCMV will no longer be unknowingly passed to patients receiving tissue donations.

Christina Evans at 11:15, 5 December 2012

Christina Evans — Wed, 05 Dec 2012 11:15:02 GMT

←Older revision		Revision as of 11:15, 5 December 2012
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	'''Stucture of Class I MHC'''		'''Stucture of Class I MHC'''

-	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> and Beta-2 microglobulin <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two α-helical regions and a bottom of antiparallel β strands. β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.	+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> and Beta-2 microglobulin <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two <scene name='User:Christina_Evans/Sandbox_1/1im3_alpha/1'>α-helical</scene> regions and a bottom of antiparallel <scene name='User:Christina_Evans/Sandbox_1/1im3_beta/1'>β strands</scene> . β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.

Christina Evans at 10:18, 5 December 2012

Christina Evans — Wed, 05 Dec 2012 10:18:06 GMT

←Older revision		Revision as of 10:18, 5 December 2012
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-	<Structure load='1im3' size='500' frame='true' align='right' caption='1IM3' scene='User:Christina_Evans/Sandbox_1/~~1im3_home_image_2~~/4' />	+	<Structure load='1im3' size='500' frame='true' align='right' caption='1IM3' scene='User:Christina_Evans/Sandbox_1/1im3_correct/2'/>


	'''Description of Class I MHC'''		'''Description of Class I MHC'''

-	Class I major histocompatibility molecules <scene name='User:Christina_Evans/Sandbox_1/~~1im3_home_image_2~~/4'>(MHC-I)</scene> are cell surface proteins that signal the presence of intracellular pathogens, such as viruses, to the host’s immune system. When viruses invade a host cell, they use the cell’s machinery to reproduce their nucleic acid and synthesize their proteins. Viral proteins, like cellular proteins, become targets for degradation and recycling, generating small portions of the viral proteins called peptides. Viral peptides of the right size can fit into the binding cleft of MHC-1 molecules, which are then displayed on the surface of the viral-infected cell. Cytotoxic T Lymphocytes (CTL), have receptors for foreign (viral) peptides complexed to MHC-1. When a CTL binds to a viral peptide-MHC-1 complex, the CTL secretes substances that lead to lysis and death of the infected cell, eventually clearing the infection. Thus, MHC-1 molecules function as an important warning system for the presence of intracellular infections. Viruses that develop a way to prevent expression of MHC-1 on the cell surface have a better chance of survival in the host.	+	Class I major histocompatibility molecules <scene name='User:Christina_Evans/Sandbox_1/1im3_correct/2'>(MHC-I)</scene> are cell surface proteins that signal the presence of intracellular pathogens, such as viruses, to the host’s immune system. When viruses invade a host cell, they use the cell’s machinery to reproduce their nucleic acid and synthesize their proteins. Viral proteins, like cellular proteins, become targets for degradation and recycling, generating small portions of the viral proteins called peptides. Viral peptides of the right size can fit into the binding cleft of MHC-1 molecules, which are then displayed on the surface of the viral-infected cell. Cytotoxic T Lymphocytes (CTL), have receptors for foreign (viral) peptides complexed to MHC-1. When a CTL binds to a viral peptide-MHC-1 complex, the CTL secretes substances that lead to lysis and death of the infected cell, eventually clearing the infection. Thus, MHC-1 molecules function as an important warning system for the presence of intracellular infections. Viruses that develop a way to prevent expression of MHC-1 on the cell surface have a better chance of survival in the host.

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	'''Stucture of Class I MHC'''		'''Stucture of Class I MHC'''

-	MHC-1 molecules are composed of two polypeptide or protein chains, an <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>α (a) chain</scene> and <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>~~β-2 microglobulin~~ (~~b2m~~)</scene>. The ~~alpha~~ chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two α-helical regions and a bottom of antiparallel β strands. β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.	+	MHC-1 molecules are composed of two polypeptide or protein chains, an alpha <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/6'>(α) chain</scene> and Beta-2 microglobulin <scene name='User:Christina_Evans/Sandbox_1/1im3_practice_4/7'>(β2m)</scene>. The α chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two α-helical regions and a bottom of antiparallel β strands. β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.