Retinoblastoma protein - Revision history

Michal Harel at 11:30, 13 February 2022

Michal Harel — Sun, 13 Feb 2022 11:30:22 GMT

←Older revision		Revision as of 11:30, 13 February 2022
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	==Retinoblastoma Protein (pRb) and E2F==		==Retinoblastoma Protein (pRb) and E2F==
-	The <scene name='Retinoblastoma_bound_to_E2F/Retinoblastoma_protein/1'>Retinoblastoma protein (pRb)</scene> weighs 110 kDa. It is a tumor suppressor protein that prevents excessive cell growth. If not mutated, it is present in our cells and blocks the growth of dysfunctional cells between the G1 and S phase of the cell cycle before they can undergo DNA replication. pRb also regulates the function of cyclin and cyclin dependent kinase (CDK) complexes which are needed for the cell to proceed with cell growth. E2F is a transcription factor that forms a complex with pRb to inhibit cell growth. When E2F is not bound to pRb it encourages cells to proliferate, it's main function is to express genes required for DNA replication to take place. Retinoblastoma protein is dependent on the transcription factor E2F, which is bound to pRb's active site when it is hypo phosphorylated. In viral cells, and in tumorous cells pRb is dysfunctional or completely lost.If there is a mutation in this gene, it's binding domain is dysfunctional and can lead to excessive cell growth, which may cause tumor or cancer development. See also [[Rtp and Tus DNA Binding]].	+	The <scene name='Retinoblastoma_bound_to_E2F/Retinoblastoma_protein/1'>Retinoblastoma protein or '''Retinoblastoma-associated protein''' (pRb)</scene> weighs 110 kDa. It is a tumor suppressor protein that prevents excessive cell growth. If not mutated, it is present in our cells and blocks the growth of dysfunctional cells between the G1 and S phase of the cell cycle before they can undergo DNA replication. pRb also regulates the function of cyclin and cyclin dependent kinase (CDK) complexes which are needed for the cell to proceed with cell growth. E2F is a transcription factor that forms a complex with pRb to inhibit cell growth. When E2F is not bound to pRb it encourages cells to proliferate, it's main function is to express genes required for DNA replication to take place. Retinoblastoma protein is dependent on the transcription factor E2F, which is bound to pRb's active site when it is hypo phosphorylated. In viral cells, and in tumorous cells pRb is dysfunctional or completely lost.If there is a mutation in this gene, it's binding domain is dysfunctional and can lead to excessive cell growth, which may cause tumor or cancer development. See also [[Rtp and Tus DNA Binding]].

	==pRb/EF binding in the cell cycle==		==pRb/EF binding in the cell cycle==

Alexander Berchansky at 12:46, 25 August 2019

Alexander Berchansky — Sun, 25 Aug 2019 12:46:39 GMT

←Older revision		Revision as of 12:46, 25 August 2019
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	==pRb/EF binding in the cell cycle==		==pRb/EF binding in the cell cycle==
	[[Image:Cell_cycle.jpg\|300px\|left\|thumb\|pRb/E2F binding in the cell cycle]]		[[Image:Cell_cycle.jpg\|300px\|left\|thumb\|pRb/E2F binding in the cell cycle]]
		+	{{Clear}}
	A cell must go through the [http://en.wikipedia.org/wiki/Cell_cycle cell cycle] in order to grow, and replicate, and before it can replicate it has to pass through the many phases of the cell cycle. The cell cycle consists of the Go phase, also known as the resting phase in which the cell exits from the		A cell must go through the [http://en.wikipedia.org/wiki/Cell_cycle cell cycle] in order to grow, and replicate, and before it can replicate it has to pass through the many phases of the cell cycle. The cell cycle consists of the Go phase, also known as the resting phase in which the cell exits from the
	cell cycle, and can remain dormant forever. Then comes the Gap-1 phase in which cell growth takes place.		cell cycle, and can remain dormant forever. Then comes the Gap-1 phase in which cell growth takes place.
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	==Specific Binding sites of pRb/E2F complex==		==Specific Binding sites of pRb/E2F complex==
-	[[Image:New fig 25.jpg\|~~right~~\|300px\|thumb\|A representation of the alpha-helices on the A and B domains that interact with E2F]]	+	[[Image:New fig 25.jpg\|left\|300px\|thumb\|A representation of the alpha-helices on the A and B domains that interact with E2F]]
		+	{{Clear}}
	When pRB and E2F form a complex, pRB is activated, and therefore inhibits cell growth. E2F is a family of transcription factors E2F-1, E2F-2, E2F-3, E2F-4, and E2F-5. Specifically, E2F-1, E2F-2, E2F-3,and E2F-4 bind to retinoblastoma during the G0,Gap-1, and S stages of the cell cycle. This complex is held together by many weak interactions, such as hydrophobic interactions, hydrogen bonds, and a salt bridge. The retinoblastoma protein’s active site is composed of two domains. <scene name='Retinoblastoma/E2F_complex/Prb_with_e2f/1'>Domains A and B</scene>, which form the pRB pocket domain that E2F can bind to, the C-terminal residues on pRb are also necessary for E2F to bind with a higher affinity. Specifically, E2F binds to the α4, α5, α6, α8, and α9 helices of the A domain, and only bind to the α11 helix of the B domain '''(see figure to the right)'''. This structure was obtained through a diffraction image from a diffractometer <ref name=Xiao>PMID: 12598654</ref>. They also found that of the entire E2F complex only the two end regions are needed to bind pRb, the marked box region and the transactivation domain which is composed of residues 243-437.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>		When pRB and E2F form a complex, pRB is activated, and therefore inhibits cell growth. E2F is a family of transcription factors E2F-1, E2F-2, E2F-3, E2F-4, and E2F-5. Specifically, E2F-1, E2F-2, E2F-3,and E2F-4 bind to retinoblastoma during the G0,Gap-1, and S stages of the cell cycle. This complex is held together by many weak interactions, such as hydrophobic interactions, hydrogen bonds, and a salt bridge. The retinoblastoma protein’s active site is composed of two domains. <scene name='Retinoblastoma/E2F_complex/Prb_with_e2f/1'>Domains A and B</scene>, which form the pRB pocket domain that E2F can bind to, the C-terminal residues on pRb are also necessary for E2F to bind with a higher affinity. Specifically, E2F binds to the α4, α5, α6, α8, and α9 helices of the A domain, and only bind to the α11 helix of the B domain '''(see figure to the right)'''. This structure was obtained through a diffraction image from a diffractometer <ref name=Xiao>PMID: 12598654</ref>. They also found that of the entire E2F complex only the two end regions are needed to bind pRb, the marked box region and the transactivation domain which is composed of residues 243-437.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>

	[[Image:6813Fig4.jpg\|left\|thumb\|E2F transcription factor]]		[[Image:6813Fig4.jpg\|left\|thumb\|E2F transcription factor]]
		+	{{Clear}}
	There are 18 residues of the E2F protein that are involved in the pRb/E2F complex '''(left figure)''', residues 409-426. Within this E2F region, there are 5 essential amino acids that if altered, would cause the complex to fall apart. These amino acids are the following: <scene name='Retinoblastoma/E2F_complex/Hydrophobic_pocket_tyr_41/2'>Tyr 411</scene> binds to pRB via a hydrophobic pocket created by phenolic ring with isoluecine amino acids on the A domain of pRb, and a hydrogen bond created by the hydroxyl group on the phenol ring. '''Leu(424)''' and '''Phe(425)''' both form many hydrophobic interactions. <scene name='Retinoblastoma/E2F_complex/Glu_419/1'>Glu-419</scene> (in light green) hydrogen bonds to Thr(645) of pRB, and <scene name='Retinoblastoma/E2F_complex/Asp_423/1'>Asp-423</scene> (in light purple) forms a salt bridge with Arg(467) on pRB <ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>. Any point mutations of any of these amino acids will block binding of pRb, leading to deactivation of pRb’s cell inhibiting function, and will allow E2F to promote the cell cycle to move on to the S-phase.		There are 18 residues of the E2F protein that are involved in the pRb/E2F complex '''(left figure)''', residues 409-426. Within this E2F region, there are 5 essential amino acids that if altered, would cause the complex to fall apart. These amino acids are the following: <scene name='Retinoblastoma/E2F_complex/Hydrophobic_pocket_tyr_41/2'>Tyr 411</scene> binds to pRB via a hydrophobic pocket created by phenolic ring with isoluecine amino acids on the A domain of pRb, and a hydrogen bond created by the hydroxyl group on the phenol ring. '''Leu(424)''' and '''Phe(425)''' both form many hydrophobic interactions. <scene name='Retinoblastoma/E2F_complex/Glu_419/1'>Glu-419</scene> (in light green) hydrogen bonds to Thr(645) of pRB, and <scene name='Retinoblastoma/E2F_complex/Asp_423/1'>Asp-423</scene> (in light purple) forms a salt bridge with Arg(467) on pRB <ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>. Any point mutations of any of these amino acids will block binding of pRb, leading to deactivation of pRb’s cell inhibiting function, and will allow E2F to promote the cell cycle to move on to the S-phase.

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	==Viral oncoproteins==		==Viral oncoproteins==
	[[Image:E1a.png\|thumb\|300px\|E1A oncoprotein disturbing pRb/E2F complex]]		[[Image:E1a.png\|thumb\|300px\|E1A oncoprotein disturbing pRb/E2F complex]]
-		+	{{Clear}}
	pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.		pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.

Joel L. Sussman at 14:19, 26 September 2017

Joel L. Sussman — Tue, 26 Sep 2017 14:19:49 GMT

←Older revision		Revision as of 14:19, 26 September 2017
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-	<StructureSection load='' size='350' side='right' scene='' caption='Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]]'>	+	<StructureSection load='1gux' size='350' side='right' scene='' caption='Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]]'>

	==Retinoblastoma Protein (pRb) and E2F==		==Retinoblastoma Protein (pRb) and E2F==

Joel L. Sussman at 14:14, 26 September 2017

Joel L. Sussman — Tue, 26 Sep 2017 14:14:39 GMT

←Older revision		Revision as of 14:14, 26 September 2017
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-	<StructureSection load='~~1gux~~' size='350' side='right' scene='' caption='Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]]'>	+	<StructureSection load='' size='350' side='right' scene='' caption='Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]]'>

	==Retinoblastoma Protein (pRb) and E2F==		==Retinoblastoma Protein (pRb) and E2F==

Michal Harel at 21:24, 25 September 2017

Michal Harel — Mon, 25 Sep 2017 21:24:07 GMT

←Older revision		Revision as of 21:24, 25 September 2017
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	*Retinoblastoma protein		*Retinoblastoma protein

-	**[[1ad6]] – hRBP domain A – human<br />	+	**[[1ad6]], [[3pom]], [[4ell]] – hRBP domain A – human<br />
		+	**[[4elj]] - hRBP<br />
	**[[2qdj]] - hRBP N terminal		**[[2qdj]] - hRBP N terminal

Alexander Berchansky at 08:02, 10 May 2017

Alexander Berchansky — Wed, 10 May 2017 08:02:18 GMT

←Older revision		Revision as of 08:02, 10 May 2017
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-	~~{{STRUCTURE_1gux\| right\| PDB~~=1gux ~~\| SCENE~~=~~\|CAPTION~~= Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]] }}	+	<StructureSection load='1gux' size='350' side='right' scene='' caption='Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]]'>

	==Retinoblastoma Protein (pRb) and E2F==		==Retinoblastoma Protein (pRb) and E2F==
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	[[Image:Beta-Lapachone.gif\|Structure of beta-lapachone\|left\|thumb]]		[[Image:Beta-Lapachone.gif\|Structure of beta-lapachone\|left\|thumb]]
		+	{{Clear}}
	Studies of the retinoblastoma protein and E2F transcription factor have been done to somehow find a treatment for cancer. A compound, β-Lapachone that comes from trees in South America, is currently used as a drug for cancer treatment. It functions to inhibit proliferation of cells by enhancing the binding of the pRb/E2F complex. It also inhibits the function of cyclin E, and cyclin dependent kinase to block pRb phosphorylation. β-Lapachone also induces cell apoptosis, and reacts with many other transcription factors to stop uncontrollable cell growth.<ref name=Yung Hyun Choi>http://www.jbmb.or.kr/jbmb/jbmb_files/%5B36-2%5D0303211840_223-229.pdf</ref>.		Studies of the retinoblastoma protein and E2F transcription factor have been done to somehow find a treatment for cancer. A compound, β-Lapachone that comes from trees in South America, is currently used as a drug for cancer treatment. It functions to inhibit proliferation of cells by enhancing the binding of the pRb/E2F complex. It also inhibits the function of cyclin E, and cyclin dependent kinase to block pRb phosphorylation. β-Lapachone also induces cell apoptosis, and reacts with many other transcription factors to stop uncontrollable cell growth.<ref name=Yung Hyun Choi>http://www.jbmb.or.kr/jbmb/jbmb_files/%5B36-2%5D0303211840_223-229.pdf</ref>.

	The pRb/E2F complex is very important for normal cell growth in our bodies, without proper function of it, humans are prone to the development of tumors, malignant cells, and cancer.		The pRb/E2F complex is very important for normal cell growth in our bodies, without proper function of it, humans are prone to the development of tumors, malignant cells, and cancer.
-		+	</StructureSection>
	==3D structures of retinoblastoma protein==		==3D structures of retinoblastoma protein==

Michal Harel at 09:49, 18 February 2016

Michal Harel — Thu, 18 Feb 2016 09:49:02 GMT

←Older revision		Revision as of 09:49, 18 February 2016
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	[[Image:E1a.png\|thumb\|300px\|E1A oncoprotein disturbing pRb/E2F complex]]		[[Image:E1a.png\|thumb\|300px\|E1A oncoprotein disturbing pRb/E2F complex]]

-	pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.	+	pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.
		+
		+	See also [[Proteins involved in cancer]].

	==Mutations of pRb==		==Mutations of pRb==

Michal Harel at 10:34, 7 December 2014

Michal Harel — Sun, 07 Dec 2014 10:34:00 GMT

←Older revision		Revision as of 10:34, 7 December 2014
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	Activation of retinoblastoma protein occurs when it is hypophosphorylated, bound to E2F, and is not mutated. When hypophosphorylated, it inactivates cdk-cyclin complexes and is tightly bound to E2F. A non mutated pRb protein can undergo proper phosphorylation and proper binding to E2F. There are also many ways to inactivate pRb, phosphorylation of pRb, interaction with viral proteins, mutation of the pRb gene, and via the Caspade-mediated degradation.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>		Activation of retinoblastoma protein occurs when it is hypophosphorylated, bound to E2F, and is not mutated. When hypophosphorylated, it inactivates cdk-cyclin complexes and is tightly bound to E2F. A non mutated pRb protein can undergo proper phosphorylation and proper binding to E2F. There are also many ways to inactivate pRb, phosphorylation of pRb, interaction with viral proteins, mutation of the pRb gene, and via the Caspade-mediated degradation.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>

-	~~'''~~Phosphorylation~~'''~~	+	==Phosphorylation==

	Phosphorylation of pRb is caused by binding of [http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin dependent kinase] and [http://en.wikipedia.org/wiki/Cyclin Cyclin] complexes such as cdk4/6-cyclin D and cdk2-cyclin E.<ref name=Nevins>PMID: 11257102</ref> This will prevent binding free pRb to E2F, or can cause the pRb/E2F complex to fall apart. Now that E2F is free, it can activate the progression of the cell though to S-phase. <scene name='Retinoblastoma/E2F_complex/Serine/1'>Ser (567)</scene> is a specific amino acid that undergoes phosphorylation, and has been observed to disrupt the A and B-domain binding site of pRb.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>		Phosphorylation of pRb is caused by binding of [http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin dependent kinase] and [http://en.wikipedia.org/wiki/Cyclin Cyclin] complexes such as cdk4/6-cyclin D and cdk2-cyclin E.<ref name=Nevins>PMID: 11257102</ref> This will prevent binding free pRb to E2F, or can cause the pRb/E2F complex to fall apart. Now that E2F is free, it can activate the progression of the cell though to S-phase. <scene name='Retinoblastoma/E2F_complex/Serine/1'>Ser (567)</scene> is a specific amino acid that undergoes phosphorylation, and has been observed to disrupt the A and B-domain binding site of pRb.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>

-	~~'''~~Viral ~~Oncoproteins'''~~	+	==Viral oncoproteins==
	[[Image:E1a.png\|thumb\|300px\|E1A oncoprotein disturbing pRb/E2F complex]]		[[Image:E1a.png\|thumb\|300px\|E1A oncoprotein disturbing pRb/E2F complex]]

	pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.		pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.

-	~~'''~~Mutations of pRb~~'''~~	+	==Mutations of pRb==

	Any mutation of the pRb gene will disrupt its proper function. If mutated, pRb can me either present and dysfunctional, or completely absent. Mutated pRb has been found in many human tumors, such as [http://en.wikipedia.org/wiki/Osteosarcoma#Variants osteosarcoma], which is a cancerous bone tumor, cell lung carcinomas and breast carcinomas that arise from cells whose genome has been altered.		Any mutation of the pRb gene will disrupt its proper function. If mutated, pRb can me either present and dysfunctional, or completely absent. Mutated pRb has been found in many human tumors, such as [http://en.wikipedia.org/wiki/Osteosarcoma#Variants osteosarcoma], which is a cancerous bone tumor, cell lung carcinomas and breast carcinomas that arise from cells whose genome has been altered.

-	~~'''~~Caspade-Mediated degradation~~'''~~	+	==Caspade-Mediated degradation==

	The Caspade-Mediated degradation is a type of cleavage that leads to pRb degradation. Lysing occurs between Asp (886) and Gly (887), which then allows a Tumor Nacrosis factor (TNF) to stimulate inhibition of pRb.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>		The Caspade-Mediated degradation is a type of cleavage that leads to pRb degradation. Lysing occurs between Asp (886) and Gly (887), which then allows a Tumor Nacrosis factor (TNF) to stimulate inhibition of pRb.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>
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	==3D structures of retinoblastoma protein==		==3D structures of retinoblastoma protein==

-	==~~=Retinoblastoma protein===~~	+	Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
		+	{{#tree:id=OrganizedByTopic\|openlevels=0\|

-	~~[[1ad6]] – hRBP domain A – human<br />~~	+	*Retinoblastoma protein
-	~~[[2qdj]] - hRBP N terminal~~	+

-	~~===Retinoblastoma protein complex with viral protein===~~	+	**[[1ad6]] – hRBP domain A – human<br />
		+	**[[2qdj]] - hRBP N terminal

-	~~[[1gux]] – hRBP pocket domain + papilloma virus peptide<br />~~	+	*Retinoblastoma protein complex with viral protein
-	~~[[1gh6]] - hRBP pocket domain + simian virus T antigen<br />~~	+
-	~~[[2r7g]] - hRBP pocket domain + adenovirus E1A~~ protein	+

-	~~===Retinoblastoma~~ protein ~~complex with transcription factor===~~	+	**[[1gux]] – hRBP pocket domain + papilloma virus peptide<br />
		+	**[[1gh6]] - hRBP pocket domain + simian virus T antigen<br />
		+	**[[2r7g]] - hRBP pocket domain + adenovirus E1A protein

-	~~[[1n4m]] - hRBP pocket domain + E2F2 transactivation domain<br />~~	+	*Retinoblastoma protein complex with transcription factor
-	~~[[1o9k]] - hRBP pocket domain + E2F1 transactivation domain<br />~~	+
-	~~[[2aze]] – hRBP C terminal + E2F1 +~~ transcription factor ~~DP1~~	+

		+	**[[1n4m]] - hRBP pocket domain + E2F2 transactivation domain<br />
		+	**[[1o9k]] - hRBP pocket domain + E2F1 transactivation domain<br />
		+	**[[2aze]] – hRBP C terminal + E2F1 + transcription factor DP1
		+	}}

	==References==		==References==

Michal Harel at 12:26, 23 September 2014

Michal Harel — Tue, 23 Sep 2014 12:26:28 GMT

←Older revision		Revision as of 12:26, 23 September 2014
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	{{STRUCTURE_1gux\| right\| PDB=1gux \| SCENE=\|CAPTION= Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]] }}		{{STRUCTURE_1gux\| right\| PDB=1gux \| SCENE=\|CAPTION= Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]] }}
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	==Retinoblastoma Protein (pRb) and E2F==		==Retinoblastoma Protein (pRb) and E2F==
	The <scene name='Retinoblastoma_bound_to_E2F/Retinoblastoma_protein/1'>Retinoblastoma protein (pRb)</scene> weighs 110 kDa. It is a tumor suppressor protein that prevents excessive cell growth. If not mutated, it is present in our cells and blocks the growth of dysfunctional cells between the G1 and S phase of the cell cycle before they can undergo DNA replication. pRb also regulates the function of cyclin and cyclin dependent kinase (CDK) complexes which are needed for the cell to proceed with cell growth. E2F is a transcription factor that forms a complex with pRb to inhibit cell growth. When E2F is not bound to pRb it encourages cells to proliferate, it's main function is to express genes required for DNA replication to take place. Retinoblastoma protein is dependent on the transcription factor E2F, which is bound to pRb's active site when it is hypo phosphorylated. In viral cells, and in tumorous cells pRb is dysfunctional or completely lost.If there is a mutation in this gene, it's binding domain is dysfunctional and can lead to excessive cell growth, which may cause tumor or cancer development. See also [[Rtp and Tus DNA Binding]].		The <scene name='Retinoblastoma_bound_to_E2F/Retinoblastoma_protein/1'>Retinoblastoma protein (pRb)</scene> weighs 110 kDa. It is a tumor suppressor protein that prevents excessive cell growth. If not mutated, it is present in our cells and blocks the growth of dysfunctional cells between the G1 and S phase of the cell cycle before they can undergo DNA replication. pRb also regulates the function of cyclin and cyclin dependent kinase (CDK) complexes which are needed for the cell to proceed with cell growth. E2F is a transcription factor that forms a complex with pRb to inhibit cell growth. When E2F is not bound to pRb it encourages cells to proliferate, it's main function is to express genes required for DNA replication to take place. Retinoblastoma protein is dependent on the transcription factor E2F, which is bound to pRb's active site when it is hypo phosphorylated. In viral cells, and in tumorous cells pRb is dysfunctional or completely lost.If there is a mutation in this gene, it's binding domain is dysfunctional and can lead to excessive cell growth, which may cause tumor or cancer development. See also [[Rtp and Tus DNA Binding]].
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	==pRb/EF binding in the cell cycle==		==pRb/EF binding in the cell cycle==
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	When pRB is phosphorylated, it no longer inhibits cell growth and the cell can continue developing. Phosphorylation of retinoblastoma is caused by the cyclin CDK complexes that are active throughout the cell cycle, in particular cyclin E an D, and cyclin dependent kinases 2, 4 and 6.		When pRB is phosphorylated, it no longer inhibits cell growth and the cell can continue developing. Phosphorylation of retinoblastoma is caused by the cyclin CDK complexes that are active throughout the cell cycle, in particular cyclin E an D, and cyclin dependent kinases 2, 4 and 6.
	It is important for retinoblastoma to function properly between the Gap-1 and S-phase, if retinoblastoma is disturbed then cell replication is not inhibited, this will allow replication of cells carrying damaged DNA.<ref name=DeGregory>http://genesdev.cshlp.org/content/9/23/2873.full.pdf</ref>		It is important for retinoblastoma to function properly between the Gap-1 and S-phase, if retinoblastoma is disturbed then cell replication is not inhibited, this will allow replication of cells carrying damaged DNA.<ref name=DeGregory>http://genesdev.cshlp.org/content/9/23/2873.full.pdf</ref>
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	==Specific Binding sites of pRb/E2F complex==		==Specific Binding sites of pRb/E2F complex==
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	[[Image:6813Fig4.jpg\|left\|thumb\|E2F transcription factor]]		[[Image:6813Fig4.jpg\|left\|thumb\|E2F transcription factor]]
	There are 18 residues of the E2F protein that are involved in the pRb/E2F complex '''(left figure)''', residues 409-426. Within this E2F region, there are 5 essential amino acids that if altered, would cause the complex to fall apart. These amino acids are the following: <scene name='Retinoblastoma/E2F_complex/Hydrophobic_pocket_tyr_41/2'>Tyr 411</scene> binds to pRB via a hydrophobic pocket created by phenolic ring with isoluecine amino acids on the A domain of pRb, and a hydrogen bond created by the hydroxyl group on the phenol ring. '''Leu(424)''' and '''Phe(425)''' both form many hydrophobic interactions. <scene name='Retinoblastoma/E2F_complex/Glu_419/1'>Glu-419</scene> (in light green) hydrogen bonds to Thr(645) of pRB, and <scene name='Retinoblastoma/E2F_complex/Asp_423/1'>Asp-423</scene> (in light purple) forms a salt bridge with Arg(467) on pRB <ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>. Any point mutations of any of these amino acids will block binding of pRb, leading to deactivation of pRb’s cell inhibiting function, and will allow E2F to promote the cell cycle to move on to the S-phase.		There are 18 residues of the E2F protein that are involved in the pRb/E2F complex '''(left figure)''', residues 409-426. Within this E2F region, there are 5 essential amino acids that if altered, would cause the complex to fall apart. These amino acids are the following: <scene name='Retinoblastoma/E2F_complex/Hydrophobic_pocket_tyr_41/2'>Tyr 411</scene> binds to pRB via a hydrophobic pocket created by phenolic ring with isoluecine amino acids on the A domain of pRb, and a hydrogen bond created by the hydroxyl group on the phenol ring. '''Leu(424)''' and '''Phe(425)''' both form many hydrophobic interactions. <scene name='Retinoblastoma/E2F_complex/Glu_419/1'>Glu-419</scene> (in light green) hydrogen bonds to Thr(645) of pRB, and <scene name='Retinoblastoma/E2F_complex/Asp_423/1'>Asp-423</scene> (in light purple) forms a salt bridge with Arg(467) on pRB <ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>. Any point mutations of any of these amino acids will block binding of pRb, leading to deactivation of pRb’s cell inhibiting function, and will allow E2F to promote the cell cycle to move on to the S-phase.
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	==Activation/ Deactivation of pRB==		==Activation/ Deactivation of pRB==
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	Phosphorylation of pRb is caused by binding of [http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin dependent kinase] and [http://en.wikipedia.org/wiki/Cyclin Cyclin] complexes such as cdk4/6-cyclin D and cdk2-cyclin E.<ref name=Nevins>PMID: 11257102</ref> This will prevent binding free pRb to E2F, or can cause the pRb/E2F complex to fall apart. Now that E2F is free, it can activate the progression of the cell though to S-phase. <scene name='Retinoblastoma/E2F_complex/Serine/1'>Ser (567)</scene> is a specific amino acid that undergoes phosphorylation, and has been observed to disrupt the A and B-domain binding site of pRb.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>		Phosphorylation of pRb is caused by binding of [http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin dependent kinase] and [http://en.wikipedia.org/wiki/Cyclin Cyclin] complexes such as cdk4/6-cyclin D and cdk2-cyclin E.<ref name=Nevins>PMID: 11257102</ref> This will prevent binding free pRb to E2F, or can cause the pRb/E2F complex to fall apart. Now that E2F is free, it can activate the progression of the cell though to S-phase. <scene name='Retinoblastoma/E2F_complex/Serine/1'>Ser (567)</scene> is a specific amino acid that undergoes phosphorylation, and has been observed to disrupt the A and B-domain binding site of pRb.<ref name=Seville>http://hosted2.roswellpark.org/o4s/audio/references/Black5_090706.pdf</ref>
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	'''Viral Oncoproteins'''		'''Viral Oncoproteins'''
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	pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.		pRb can interact with viral oncoproteins. These viral oncoproteins contain a strictly conserved LXCXE motif that allows them to bind to the retinoblastoma A and B pocket domain or at any other sites of the pRb protein such as the c-terminal. Binding of a viral protein out competes binding of E2F, therefore causing E2F to detach from pRb.. Examples of these viral genes are E7 oncoprotein of the [http://en.wikipedia.org/wiki/Human_papillomavirus Human papillomavirus (HPV)], the [http://en.wikipedia.org/wiki/Adenoviridae adenovirus E1A] which encodes potential oncoproteins that alter cell control, and the [http://en.wikipedia.org/wiki/SV40 SV40 antigen] which is a DNA virus that can cause tumors.<ref name=Liu>PMID:17974914</ref>. The figure to the right shows binding of E1A adenovirus to pRb, and displacement of E2F. E1A binds deep within the A and B pocket domains, mainly it binds to alpha-4,5,6,8, and 11 helices of the pocket domain<ref name=Liu>PMID:17974914</ref> Biding of viral oncoproteins disrupts the pRb/E2F complex, allowing E2F to activate the cell cycle.
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	'''Mutations of pRb'''		'''Mutations of pRb'''

	Any mutation of the pRb gene will disrupt its proper function. If mutated, pRb can me either present and dysfunctional, or completely absent. Mutated pRb has been found in many human tumors, such as [http://en.wikipedia.org/wiki/Osteosarcoma#Variants osteosarcoma], which is a cancerous bone tumor, cell lung carcinomas and breast carcinomas that arise from cells whose genome has been altered.		Any mutation of the pRb gene will disrupt its proper function. If mutated, pRb can me either present and dysfunctional, or completely absent. Mutated pRb has been found in many human tumors, such as [http://en.wikipedia.org/wiki/Osteosarcoma#Variants osteosarcoma], which is a cancerous bone tumor, cell lung carcinomas and breast carcinomas that arise from cells whose genome has been altered.
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	'''Caspade-Mediated degradation'''		'''Caspade-Mediated degradation'''
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	The pRb/E2F complex is very important for normal cell growth in our bodies, without proper function of it, humans are prone to the development of tumors, malignant cells, and cancer.		The pRb/E2F complex is very important for normal cell growth in our bodies, without proper function of it, humans are prone to the development of tumors, malignant cells, and cancer.

		+	==3D structures of retinoblastoma protein==

-		+	===Retinoblastoma protein===
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-	==~~3D structures of retinoblastoma~~ protein==	+

	[[1ad6]] – hRBP domain A – human<br />		[[1ad6]] – hRBP domain A – human<br />

Michal Harel at 09:29, 14 November 2012

Michal Harel — Wed, 14 Nov 2012 09:29:07 GMT

←Older revision		Revision as of 09:29, 14 November 2012
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-	{{STRUCTURE_1gux\| right\| PDB=1gux \| SCENE=\|CAPTION= Human ~~Ras GTPase activating~~ protein ~~dimer. SH3~~ domain, [[1gux]] }}	+	{{STRUCTURE_1gux\| right\| PDB=1gux \| SCENE=\|CAPTION= Human retinoblastoma protein pocket domain dimer (grey and green) complex with papilloma virus E7 peptide (magenta) , [[1gux]] }}