7DNJ

K63-polyUb MDA5CARDs complex

Summary for 7DNJ

• Entry DOI: 10.2210/pdb7dnj/pdb
• EMDB information: 30785
• Descriptor: Interferon-induced helicase C domain-containing protein 1, Ubiquitin (2 entities in total)
• Functional Keywords: signaling complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 163918.18

Authors

Song, B.,Chen, Y.,Luo, D.H.,Zheng, J. (deposition date: 2020-12-09, release date: 2021-10-13, Last modification date: 2025-07-02)

Primary citation

Song, B.,Chen, Y.,Liu, X.,Yuan, F.,Tan, E.Y.J.,Lei, Y.,Song, N.,Han, Y.,Pascal, B.D.,Griffin, P.R.,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, 54:2218-, 2021

PubMed Abstract: 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 ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (CARDs). Cryoelectron microscopy structures of a polyUb-bound CARDs tetramer and a polyUb-bound CARDs-CARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging CARDs and 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.

PubMed: 34644557
DOI: 10.1016/j.immuni.2021.09.008

Experimental method

ELECTRON MICROSCOPY (3.3 Å)