2rqb

From Proteopedia

(Difference between revisions)

Current revision

Solution structure of MDA5 CTD

Structural highlights

2rqb is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IFIH1_HUMAN Genetic variation in IFIH1 is associated with diabetes mellitus insulin-dependent type 19 (IDDM19) [MIM:610155. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.^[1] Note=IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD).^[2] ^[3]

Function

IFIH1_HUMAN Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Its ligands include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines.^[4] ^[5] ^[6] ^[7] ^[8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The RIG-I like receptor (RLR) comprises three homologues: RIG-I (retinoic acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5), and LGP2 (laboratory of genetics and physiology 2). Each RLR senses different viral infections by recognizing replicating viral RNA in the cytoplasm. The RLR contains a conserved C-terminal domain (CTD), which is responsible for the binding specificity to the viral RNAs, including double-stranded RNA (dsRNA) and 5'-triphosphated single-stranded RNA (5'ppp-ssRNA). Here, the solution structures of the MDA5 and LGP2 CTD domains were solved by NMR and compared with those of RIG-I CTD. The CTD domains each have a similar fold and a similar basic surface but there is the distinct structural feature of a RNA binding loop; The LGP2 and RIG-I CTD domains have a large basic surface, one bank of which is formed by the RNA binding loop. MDA5 also has a large basic surface that is extensively flat due to open conformation of the RNA binding loop. The NMR chemical shift perturbation study showed that dsRNA and 5'ppp-ssRNA are bound to the basic surface of LGP2 CTD, whereas dsRNA is bound to the basic surface of MDA5 CTD but much more weakly, indicating that the conformation of the RNA binding loop is responsible for the sensitivity to dsRNA and 5'ppp-ssRNA. Mutation study of the basic surface and the RNA binding loop supports the conclusion from the structure studies. Thus, the CTD is responsible for the binding affinity to the viral RNAs.

Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors.,Takahasi K, Kumeta H, Tsuduki N, Narita R, Shigemoto T, Hirai R, Yoneyama M, Horiuchi M, Ogura K, Fujita T, Inagaki F J Biol Chem. 2009 Jun 26;284(26):17465-74. Epub 2009 Apr 20. PMID:19380577^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, Guja C, Ionescu-Tirgoviste C, Widmer B, Dunger DB, Savage DA, Walker NM, Clayton DG, Todd JA. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet. 2006 Jun;38(6):617-9. Epub 2006 May 14. PMID:16699517 doi:10.1038/ng1800
↑ Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, Fujita T, Kuwana M. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease. Arthritis Rheum. 2009 Jul;60(7):2193-200. doi: 10.1002/art.24621. PMID:19565506 doi:10.1002/art.24621
↑ Nakashima R, Imura Y, Kobayashi S, Yukawa N, Yoshifuji H, Nojima T, Kawabata D, Ohmura K, Usui T, Fujii T, Okawa K, Mimori T. The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody. Rheumatology (Oxford). 2010 Mar;49(3):433-40. doi: 10.1093/rheumatology/kep375., Epub 2009 Dec 16. PMID:20015976 doi:10.1093/rheumatology/kep375
↑ Cocude C, Truong MJ, Billaut-Mulot O, Delsart V, Darcissac E, Capron A, Mouton Y, Bahr GM. A novel cellular RNA helicase, RH116, differentially regulates cell growth, programmed cell death and human immunodeficiency virus type 1 replication. J Gen Virol. 2003 Dec;84(Pt 12):3215-25. PMID:14645903
↑ Bamming D, Horvath CM. Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I, and LGP2. J Biol Chem. 2009 Apr 10;284(15):9700-12. doi: 10.1074/jbc.M807365200. Epub 2009 , Feb 11. PMID:19211564 doi:10.1074/jbc.M807365200
↑ Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kato H, Takeuchi O, Akira S, Way M, Schiavo G, Reis e Sousa C. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol. 2009 Oct;83(20):10761-9. doi: 10.1128/JVI.00770-09. Epub 2009 Aug 5. PMID:19656871 doi:10.1128/JVI.00770-09
↑ Jiang M, Osterlund P, Sarin LP, Poranen MM, Bamford DH, Guo D, Julkunen I. Innate immune responses in human monocyte-derived dendritic cells are highly dependent on the size and the 5' phosphorylation of RNA molecules. J Immunol. 2011 Aug 15;187(4):1713-21. doi: 10.4049/jimmunol.1100361. Epub 2011, Jul 8. PMID:21742966 doi:10.4049/jimmunol.1100361
↑ Zust R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, Szretter KJ, Baker SC, Barchet W, Diamond MS, Siddell SG, Ludewig B, Thiel V. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol. 2011 Feb;12(2):137-43. doi: 10.1038/ni.1979. Epub 2011 Jan 9. PMID:21217758 doi:10.1038/ni.1979
↑ Takahasi K, Kumeta H, Tsuduki N, Narita R, Shigemoto T, Hirai R, Yoneyama M, Horiuchi M, Ogura K, Fujita T, Inagaki F. Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors. J Biol Chem. 2009 Jun 26;284(26):17465-74. Epub 2009 Apr 20. PMID:19380577 doi:10.1074/jbc.M109.007179

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2rqb"

@@ Line 1: / Line 1: @@
-{{STRUCTURE_2rqb|  PDB=2rqb  |  SCENE=  }}
-===Solution structure of MDA5 CTD===
-{{ABSTRACT_PUBMED_19380577}}
-==Disease==
+==Solution structure of MDA5 CTD==
-[[http://www.uniprot.org/uniprot/IFIH1_HUMAN IFIH1_HUMAN]] Genetic variation in IFIH1 is associated with diabetes mellitus insulin-dependent type 19 (IDDM19) [MIM:[http://omim.org/entry/610155 610155]]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:16699517</ref>  Note=IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD).<ref>PMID:19565506</ref><ref>PMID:20015976</ref>
+<StructureSection load='2rqb' size='340' side='right'caption='[[2rqb]]' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2rqb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RQB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2RQB FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2rqb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rqb OCA], [https://pdbe.org/2rqb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2rqb RCSB], [https://www.ebi.ac.uk/pdbsum/2rqb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2rqb ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/IFIH1_HUMAN IFIH1_HUMAN] Genetic variation in IFIH1 is associated with diabetes mellitus insulin-dependent type 19 (IDDM19) [MIM:[https://omim.org/entry/610155 610155]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:16699517</ref>   Note=IFIH1 is the CADM-140 autoantigen, involved in clinically amyopathic dermatomyositis (CADM). This is a chronic inflammatory disorder that shows typical skin manifestations of dermatomyositis but has no or little evidence of clinical myositis. Anti-CADM-140 antibodies appear to be specific to dermatomyositis, especially CADM. Patients with anti-CADM-140 antibodies frequently develop life-threatening acute progressive interstitial lung disease (ILD).<ref>PMID:19565506</ref> <ref>PMID:20015976</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/IFIH1_HUMAN IFIH1_HUMAN] Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Its ligands include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines.<ref>PMID:14645903</ref> <ref>PMID:19211564</ref> <ref>PMID:19656871</ref> <ref>PMID:21742966</ref> <ref>PMID:21217758</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rq/2rqb_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2rqb ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The RIG-I like receptor (RLR) comprises three homologues: RIG-I (retinoic acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5), and LGP2 (laboratory of genetics and physiology 2). Each RLR senses different viral infections by recognizing replicating viral RNA in the cytoplasm. The RLR contains a conserved C-terminal domain (CTD), which is responsible for the binding specificity to the viral RNAs, including double-stranded RNA (dsRNA) and 5'-triphosphated single-stranded RNA (5'ppp-ssRNA). Here, the solution structures of the MDA5 and LGP2 CTD domains were solved by NMR and compared with those of RIG-I CTD. The CTD domains each have a similar fold and a similar basic surface but there is the distinct structural feature of a RNA binding loop; The LGP2 and RIG-I CTD domains have a large basic surface, one bank of which is formed by the RNA binding loop. MDA5 also has a large basic surface that is extensively flat due to open conformation of the RNA binding loop. The NMR chemical shift perturbation study showed that dsRNA and 5'ppp-ssRNA are bound to the basic surface of LGP2 CTD, whereas dsRNA is bound to the basic surface of MDA5 CTD but much more weakly, indicating that the conformation of the RNA binding loop is responsible for the sensitivity to dsRNA and 5'ppp-ssRNA. Mutation study of the basic surface and the RNA binding loop supports the conclusion from the structure studies. Thus, the CTD is responsible for the binding affinity to the viral RNAs.
-==Function==
+Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors.,Takahasi K, Kumeta H, Tsuduki N, Narita R, Shigemoto T, Hirai R, Yoneyama M, Horiuchi M, Ogura K, Fujita T, Inagaki F J Biol Chem. 2009 Jun 26;284(26):17465-74. Epub 2009 Apr 20. PMID:19380577<ref>PMID:19380577</ref>
-[[http://www.uniprot.org/uniprot/IFIH1_HUMAN IFIH1_HUMAN]] Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Its ligands include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines.<ref>PMID:14645903</ref><ref>PMID:19211564</ref><ref>PMID:19656871</ref><ref>PMID:21742966</ref><ref>PMID:21217758</ref>
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[2rqb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RQB OCA].
+</div>
+<div class="pdbe-citations 2rqb" style="background-color:#fffaf0;"></div>
-==Reference==
+== References ==
-<ref group="xtra">PMID:019380577</ref><references group="xtra"/><references/>
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Fujita, T.]]
+[[Category: Large Structures]]
-[[Category: Fuyuhiko, I.]]
+[[Category: Fujita T]]
-[[Category: Hirai, R.]]
+[[Category: Fuyuhiko I]]
-[[Category: Horiuchi, M.]]
+[[Category: Hirai R]]
-[[Category: Kumeta, H.]]
+[[Category: Horiuchi M]]
-[[Category: Narita, R.]]
+[[Category: Kumeta H]]
-[[Category: Ogura, K.]]
+[[Category: Narita R]]
-[[Category: Shigemoto, T.]]
+[[Category: Ogura K]]
-[[Category: Takahasi, K.]]
+[[Category: Shigemoto T]]
-[[Category: Tsuduki, N.]]
+[[Category: Takahasi K]]
-[[Category: Yoneyama, M.]]
+[[Category: Tsuduki N]]
-[[Category: Antiviral defense]]
+[[Category: Yoneyama M]]
-[[Category: Atp-binding]]
-[[Category: Diabetes mellitus]]
-[[Category: Helicase]]
-[[Category: Host-virus interaction]]
-[[Category: Hydrolase]]
-[[Category: Immune response]]
-[[Category: Innate immunity]]
-[[Category: Nucleotide-binding]]
-[[Category: Nucleus]]
-[[Category: Phosphoprotein]]
-[[Category: Rna binding protein]]
-[[Category: Rna-binding]]

2rqb

From Proteopedia

Current revision

Solution structure of MDA5 CTD

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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