7dni
From Proteopedia
MDA5 CARDs-MAVS CARD polyUb complex
Structural highlights
FunctionUBB_HUMAN Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] [2] 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Chen Y | Luo DH | Song B | Zheng J
