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==== | ==K63-polyUb MDA5CARDs complex== | ||
<StructureSection load='7dnj' size='340' side='right'caption='[[7dnj]]' scene=''> | <StructureSection load='7dnj' size='340' side='right'caption='[[7dnj]], [[Resolution|resolution]] 3.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7dnj]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DNJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DNJ FirstGlance]. <br> | ||
</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=7dnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dnj OCA], [https://pdbe.org/7dnj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dnj RCSB], [https://www.ebi.ac.uk/pdbsum/7dnj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dnj ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3Å</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=7dnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dnj OCA], [https://pdbe.org/7dnj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dnj RCSB], [https://www.ebi.ac.uk/pdbsum/7dnj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dnj ProSAT]</span></td></tr> | |||
</table> | </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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUb(n) (n >/= 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 ((MDA5)CARDs). Cryoelectron microscopy structures of a polyUb(13)-bound (MDA5)CARDs tetramer and a polyUb(11)-bound (MDA5)CARDs-(MAVS)CARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging (MDA5)CARDs and (MAVS)CARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses. | |||
Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.,Song B, Chen Y, Liu X, Yuan F, Tan EYJ, Lei Y, Song N, Han Y, Pascal BD, Griffin PR, Luo C, Wu B, Luo D, Zheng J Immunity. 2021 Oct 12;54(10):2218-2230.e5. doi: 10.1016/j.immuni.2021.09.008. PMID:34644557<ref>PMID:34644557</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7dnj" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[3D structures of ubiquitin|3D structures of ubiquitin]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Chen Y]] | ||
[[Category: Luo DH]] | |||
[[Category: Song B]] | |||
[[Category: Zheng J]] | |||
Latest revision as of 22:32, 29 May 2024
K63-polyUb MDA5CARDs complexK63-polyUb MDA5CARDs complex
Structural highlights
DiseaseIFIH1_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] FunctionIFIH1_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] Publication Abstract from PubMedThe RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUb(n) (n >/= 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 ((MDA5)CARDs). Cryoelectron microscopy structures of a polyUb(13)-bound (MDA5)CARDs tetramer and a polyUb(11)-bound (MDA5)CARDs-(MAVS)CARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging (MDA5)CARDs and (MAVS)CARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses. Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.,Song B, Chen Y, Liu X, Yuan F, Tan EYJ, Lei Y, Song N, Han Y, Pascal BD, Griffin PR, Luo C, Wu B, Luo D, Zheng J Immunity. 2021 Oct 12;54(10):2218-2230.e5. doi: 10.1016/j.immuni.2021.09.008. PMID:34644557[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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