Proteopedia

7dnj

K63-polyUb MDA5CARDs complexK63-polyUb MDA5CARDs complex

Structural highlights

7dnj is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.3Å
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]

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[9]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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. Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains. Immunity. 2021 Oct 12;54(10):2218-2230.e5. PMID:34644557 doi:10.1016/j.immuni.2021.09.008

7dnj, resolution 3.30Å

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