Interferon

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[[Image:InterferonSignalingPathway.png|600px|right|thumb|Interferon Pathway<ref name="Isaacs">[http://www.jbc.org/content/282/28/20045.full?sid=cbf08059-44d4-4957-8ea7-0351cab9c2ac] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." ''J Biol Chem'' 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200</ref>]]
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[[Image:InterferonSignalingPathway.png|600px|right|thumb|Interferon JAK-STAT Pathway showing interferons types I, II, and III<ref name="Isaacs">[http://www.jbc.org/content/282/28/20045.full?sid=cbf08059-44d4-4957-8ea7-0351cab9c2ac] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." ''J Biol Chem'' 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200</ref>]]
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'''Interferons''' were the first cytokines discovered and were identified by Isaacs and Lindenmann. These proteins were classified as interferons because they interfered with virus growth.<ref name="Isaacs" /> The initial experiments performed poorly characterized the interferons, and was based merely on bioactivity. Advances in scientific instrumentation and technique have allowed for greater understanding and visualization of not only the structure but also the mechanisms of the various types of inteferons.<ref name="Structure">PMID:2413490</ref>
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'''Interferons''' were the first cytokines discovered and were identified by Isaacs and Lindenmann. These proteins were classified as interferons because they interfered with virus growth.<ref name="Isaacs" /> The initial experiments performed poorly characterized the interferons, and was based merely on bioactivity. Advances in scientific instrumentation and technique have allowed for greater understanding and visualization of not only the structure but also the mechanisms of the various types of inteferons.<ref name="Structure">PMID:2413490</ref> The interferons were originally classified as leukocyte (interferon-α), fibroblast (interferon-β), and immmune (interferon-γ), although today they are classified into types I (α, β, ε, κ, ω), II (γ), and III (λ).<ref name="Structure" /><ref name="Isaacs" />
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The interferons were originally classified as leukocyte (interferon-α), fibroblast (interferon-β), and immmune (interferon-γ), although today they are classified into types I (α and β) and II (γ). This classification serves to give a better understanding of the similarities between α and β that does not exist between these type I interferons and interferon-γ.<ref name="Structure" /> In addition to interferons-α and -β, type I interferons also encompass three other differentiable proteins: interferon-ε, interferon-κ, and interferon-ω.
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==Signaling and Receptors==
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The signaling pathways of interferons are interesting as type I interferons share the same receptors IFNAR1 and IFNAR2. Type II interferon-γ has receptors IFNGR1 and IFNGR2, but needs two interferon-γ to signal, as illustrated in the image to the right. Interestingly enough, types I and III act together in the JAK-STAT pathway, while type II acts alone. Interferon-α and -β bind to the same receptors as one another, the affinities with which they bind to IFNAR1 and IFNAR2 differ. While the binding to IFNAR2 is stronger for both in comparison to IFNAR1, interferon-β has a much stronger affinity for IFNAR1 than interferon-α.<ref name="Interferon Receptor Interferon Alpha">PMID:17001036</ref>
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Interferon-α <scene name='Multiple_sclerosis/Ifnawithreceptorcolored/1'>binds</scene> to an interferon receptor mainly with helices C and G. There are many <scene name='Multiple_sclerosis/Ifnawithreceptorintrxns/2'>residues</scene> within 4 angstroms of one another. These residues could form many <scene name='Multiple_sclerosis/Ifnawithreceptorintrxns/5'>different types of bonds</scene>, illustrated in white dotted lines. Given that interferon-α does not undergo many structural changes upon binding to interferon receptor II, Quadt-Akabayov et al. have concluded that the binding mechanism is similar to that of a lock and key. Interferons -α and -β interact with a receptor at the cell surface.<ref>[http://www.jbc.org/content/282/28/20045.full?sid=cbf08059-44d4-4957-8ea7-0351cab9c2ac] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." ''J Biol Chem'' 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200</ref> This receptor has <scene name='Multiple_sclerosis/Ifnr_domains_labeled/1'>three domains</scene>: an
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<scene name='Multiple_sclerosis/Ifnr_n_domain_labeled/1'>N-domain</scene>, with two disulfide bonds, a <scene name='Multiple_sclerosis/Ifnr_c_domain_labeled/1'>C-domain</scene>, with one disulfide bond, and a <scene name='Multiple_sclerosis/Ifnr_linker_region_labeled/1'>linker region</scene>. The <scene name='Multiple_sclerosis/Ifnr_termini_labeled/1'>termini regions</scene> of the receptor have no secondary structure, allowing for some serious flexibility, leading to <scene name='Multiple_sclerosis/Ifnr_clash_n-c/1'>eight clashes amongst the domains</scene>.<ref name="Interferon Receptor Structure">PMID:12842042</ref>
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There are two
 
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===Interferon-α===
===Interferon-α===
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Interferon alpha has a 31% sequence homology to interferon beta. It, too, has many <scene name='Multiple_sclerosis/Ifna_labeled/1'>identifiable regions</scene> with two <scene name='Multiple_sclerosis/Ifna_disulfide_bonds/1'>disulfide bonds</scene>: one between the <scene name='Multiple_sclerosis/Ifna_disulfide_bondsn-e/1'>N-terminus and Helix E</scene>, and the other between <scene name='Multiple_sclerosis/Ifna_disulfide_bonds_ab-g/1'>Loop AB and Helix G</scene>. It has seven <scene name='Multiple_sclerosis/Ifna_alphahelices/1'>alpha helices</scene>, as compared to the five of interferon-β, and therefore has several more <scene name='Multiple_sclerosis/Ifna_loops_regions/1'>loop regions.</scene> The helices A, C, and F run <scene name='Multiple_sclerosis/Ifna_parallelacf/2'>parallel</scene> to one another, and <scene name='Multiple_sclerosis/Ifna_antiparallel/1'>anti-parallel</scene> to B, E, and G which run <scene name='Multiple_sclerosis/Ifna_parallel_beg/2'>parallel</scene> to each other.
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Interferon alpha has many <scene name='Multiple_sclerosis/Ifna_labeled/1'>identifiable regions</scene> with two <scene name='Multiple_sclerosis/Ifna_disulfide_bonds/1'>disulfide bonds</scene>: one between the <scene name='Multiple_sclerosis/Ifna_disulfide_bondsn-e/1'>N-terminus and Helix E</scene>, and the other between <scene name='Multiple_sclerosis/Ifna_disulfide_bonds_ab-g/1'>Loop AB and Helix G</scene>. It has seven <scene name='Multiple_sclerosis/Ifna_alphahelices/1'>alpha helices</scene> and has several <scene name='Multiple_sclerosis/Ifna_loops_regions/1'>loop regions.</scene> The helices A, C, and F run <scene name='Multiple_sclerosis/Ifna_parallelacf/2'>parallel</scene> to one another, and <scene name='Multiple_sclerosis/Ifna_antiparallel/1'>anti-parallel</scene> to B, E, and G which run <scene name='Multiple_sclerosis/Ifna_parallel_beg/2'>parallel</scene> to each other.
<scene name='Multiple_sclerosis/Ifna_notparalleltoanyoned/1'>Helix D</scene> does not run parallel or anti-parallel to either set, but rather runs at a 45-90 degree angle to them. Helix A consists of residues 10-12; Helix B of 40-43; Helix C of 53-68; Helix D of 70-75; Helix E of 78-100; Helix F of 109-132; and Helix G of 137-158.
<scene name='Multiple_sclerosis/Ifna_notparalleltoanyoned/1'>Helix D</scene> does not run parallel or anti-parallel to either set, but rather runs at a 45-90 degree angle to them. Helix A consists of residues 10-12; Helix B of 40-43; Helix C of 53-68; Helix D of 70-75; Helix E of 78-100; Helix F of 109-132; and Helix G of 137-158.
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Interferon-α <scene name='Multiple_sclerosis/Ifnawithreceptorcolored/1'>binds</scene> to an interferon receptor mainly with helices C and G. There are many <scene name='Multiple_sclerosis/Ifnawithreceptorintrxns/2'>residues</scene> within 4 angstroms of one another. These residues could form many <scene name='Multiple_sclerosis/Ifnawithreceptorintrxns/5'>different types of bonds</scene>, illustrated in white dotted lines. Given that interferon-α does not undergo many structural changes upon binding to interferon receptor II, Quadt-Akabayov et al. have concluded that the binding mechanism is similar to that of a lock and key. While interferon-α and -β bind to the same receptors as one another, the affinities with which they bind to IFNAR1 and IFNAR2 differ. While the binding to IFNAR2 is stronger for both in comparison to IFNAR1, interferon-β has a much stronger affinity for IFNAR1 than interferon-α.<ref name="Interferon Receptor Interferon Alpha">PMID:17001036</ref>
 
===Interferon-β===
===Interferon-β===
<scene name='Multiple_sclerosis/Interferon_beta/9'>Interferon-β</scene> is a protein growth factor that stimulates an antiviral defense. Its encoding gene is one of only two known vertebrate structural genes that lacks introns.<ref name="Biochem Text">Voet, D., Voet, J.G., and C. Pratt. ''Fundamentals of Biochemistry'' 3rd Edition. Hoboken, NJ: John Wiley and Sons, 2008. Print.</ref>
<scene name='Multiple_sclerosis/Interferon_beta/9'>Interferon-β</scene> is a protein growth factor that stimulates an antiviral defense. Its encoding gene is one of only two known vertebrate structural genes that lacks introns.<ref name="Biochem Text">Voet, D., Voet, J.G., and C. Pratt. ''Fundamentals of Biochemistry'' 3rd Edition. Hoboken, NJ: John Wiley and Sons, 2008. Print.</ref>
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Interferon-β is a relatively simple biological response modifier, with several <scene name='Multiple_sclerosis/Interferon_beta_labeled/1'>identifiable regions</scene>. It consists of five <scene name='Multiple_sclerosis/Ifnb_helices_in_color/1'>alpha helices</scene>, as well as multiple interconnecting <scene name='Multiple_sclerosis/Interferon_beta_loops/2'>loop regions</scene>. Helices A, B and D run <scene name='Multiple_sclerosis/Ifnb_parallel_abd/3'>parallel to one another</scene>, and helices C and E run <scene name='Multiple_sclerosis/Ifnb_antiparallel/1'>anti-parallel</scene> to the other three helices, but <scene name='Multiple_sclerosis/Ifnb_antiparallel_ce/3'>parallel</scene> to one another. Helix A consists of residues 6-23; Helix B consists of residues 49-65; Helix C consists of residues 77-91; Helix D consists of residues 112-131; and Helix E consists of residues 135-155.<ref name="Structure Ifn B">PMID:20616576</ref><ref name="UniProt">http://www.uniprot.org/uniprot/P00784</ref>
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Interferon-β has a 31% sequence homology to interferon-α . It is a relatively simple biological response modifier, with several <scene name='Multiple_sclerosis/Interferon_beta_labeled/1'>identifiable regions</scene>. It consists of five <scene name='Multiple_sclerosis/Ifnb_helices_in_color/1'>alpha helices</scene>, as compared to the seven of interferon-α, as well as multiple interconnecting <scene name='Multiple_sclerosis/Interferon_beta_loops/2'>loop regions</scene>. Helices A, B and D run <scene name='Multiple_sclerosis/Ifnb_parallel_abd/3'>parallel to one another</scene>, and helices C and E run <scene name='Multiple_sclerosis/Ifnb_antiparallel/1'>anti-parallel</scene> to the other three helices, but <scene name='Multiple_sclerosis/Ifnb_antiparallel_ce/3'>parallel</scene> to one another. Helix A consists of residues 6-23; Helix B consists of residues 49-65; Helix C consists of residues 77-91; Helix D consists of residues 112-131; and Helix E consists of residues 135-155.<ref name="Structure Ifn B">PMID:20616576</ref><ref name="UniProt">http://www.uniprot.org/uniprot/P00784</ref>
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Interferons -α and -β interact with a receptor at the cell surface.<ref>[http://www.jbc.org/content/282/28/20045.full?sid=cbf08059-44d4-4957-8ea7-0351cab9c2ac] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." ''J Biol Chem'' 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200</ref> This receptor has <scene name='Multiple_sclerosis/Ifnr_domains_labeled/1'>three domains</scene>: an
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<scene name='Multiple_sclerosis/Ifnr_n_domain_labeled/1'>N-domain</scene>, with two disulfide bonds, a <scene name='Multiple_sclerosis/Ifnr_c_domain_labeled/1'>C-domain</scene>, with one disulfide bond, and a <scene name='Multiple_sclerosis/Ifnr_linker_region_labeled/1'>linker region</scene>. The <scene name='Multiple_sclerosis/Ifnr_termini_labeled/1'>termini regions</scene> of the receptor have no secondary structure, allowing for some serious flexibility, leading to <scene name='Multiple_sclerosis/Ifnr_clash_n-c/1'>eight clashes amongst the domains</scene>.<ref name="Interferon Receptor Structure">PMID:12842042</ref>
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==Type II==
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==Type II (γ)==
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==Interferon-γ==
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==Type III (λ)==
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Revision as of 01:01, 24 April 2012

Interferon JAK-STAT Pathway showing interferons types I, II, and III
Interferon JAK-STAT Pathway showing interferons types I, II, and III[1]

Interferons were the first cytokines discovered and were identified by Isaacs and Lindenmann. These proteins were classified as interferons because they interfered with virus growth.[1] The initial experiments performed poorly characterized the interferons, and was based merely on bioactivity. Advances in scientific instrumentation and technique have allowed for greater understanding and visualization of not only the structure but also the mechanisms of the various types of inteferons.[2] The interferons were originally classified as leukocyte (interferon-α), fibroblast (interferon-β), and immmune (interferon-γ), although today they are classified into types I (α, β, ε, κ, ω), II (γ), and III (λ).[2][1]

Signaling and Receptors

The signaling pathways of interferons are interesting as type I interferons share the same receptors IFNAR1 and IFNAR2. Type II interferon-γ has receptors IFNGR1 and IFNGR2, but needs two interferon-γ to signal, as illustrated in the image to the right. Interestingly enough, types I and III act together in the JAK-STAT pathway, while type II acts alone. Interferon-α and -β bind to the same receptors as one another, the affinities with which they bind to IFNAR1 and IFNAR2 differ. While the binding to IFNAR2 is stronger for both in comparison to IFNAR1, interferon-β has a much stronger affinity for IFNAR1 than interferon-α.[3]

Interferon-α to an interferon receptor mainly with helices C and G. There are many within 4 angstroms of one another. These residues could form many , illustrated in white dotted lines. Given that interferon-α does not undergo many structural changes upon binding to interferon receptor II, Quadt-Akabayov et al. have concluded that the binding mechanism is similar to that of a lock and key. Interferons -α and -β interact with a receptor at the cell surface.[4] This receptor has : an , with two disulfide bonds, a , with one disulfide bond, and a . The of the receptor have no secondary structure, allowing for some serious flexibility, leading to .[5]


Click on the green links to the left to view the structural aspects of interferons. PDB ID: 2hym)

Drag the structure with the mouse to rotate


References

  1. ↑ 1.0 1.1 1.2 [1] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." J Biol Chem 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200
  2. ↑ 2.0 2.1 Langer JA, Pestka S. Structure of interferons. Pharmacol Ther. 1985;27(3):371-401. PMID:2413490
  3. ↑ Quadt-Akabayov SR, Chill JH, Levy R, Kessler N, Anglister J. Determination of the human type I interferon receptor binding site on human interferon-alpha2 by cross saturation and an NMR-based model of the complex. Protein Sci. 2006 Nov;15(11):2656-68. Epub 2006 Sep 25. PMID:17001036 doi:10.1110/ps.062283006
  4. ↑ [2] Samuel, C.E. "Interferons, Interferon Receptors, Signal Transducer and Transcriptional Activators, and Inteferon Regulatory Factors." J Biol Chem 2007 282: 20045-20046. First Published on May 14, 2007, doi:10.1074/jbc.R700025200
  5. ↑ Chill JH, Quadt SR, Levy R, Schreiber G, Anglister J. The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding. Structure. 2003 Jul;11(7):791-802. PMID:12842042
  6. ↑ Quadt-Akabayov SR, Chill JH, Levy R, Kessler N, Anglister J. Determination of the human type I interferon receptor binding site on human interferon-alpha2 by cross saturation and an NMR-based model of the complex. Protein Sci. 2006 Nov;15(11):2656-68. Epub 2006 Sep 25. PMID:17001036 doi:10.1110/ps.062283006
  7. ↑ Voet, D., Voet, J.G., and C. Pratt. Fundamentals of Biochemistry 3rd Edition. Hoboken, NJ: John Wiley and Sons, 2008. Print.
  8. ↑ Kudo M. Management of hepatocellular carcinoma: from prevention to molecular targeted therapy. Oncology. 2010 Jul;78 Suppl 1:1-6. Epub 2010 Jul 8. PMID:20616576 doi:10.1159/000315222
  9. ↑ http://www.uniprot.org/uniprot/P00784

Relevant 3D Structures

Interferon-α

1rh2, 1itf - Homo sapiens

Interferon-β

1au1 - Homo sapiens

1ifa, 1wu3 - Mus musculus

Inteferon-α/β Receptors

3s8w, 3s98 - Homo sapiens

Interferon-α/β Receptors in Complex with Interferon-α

3oq3, 3se3, 3se4, 1n6u, 1n6v, 2hym, 2kz1, 2lag, 3s9d - Homo sapiens


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