Structural Basis for dsRNA Recognition, Filament Formation, and Antiviral Signal Activation by MDA5

Bin Wu, Alys Peisley, Claire Richards, Hui Yao, Xiaohui Zeng, Cecilie Lin, Feixia Chu, Thomas Walz, and Sun Hur

Cell. 152, 276-289 (2013)

Speaker: Tao-Sheng Liu (劉道生)                         Time: 14:00~15:00, May. 15, 2013

Commentator: Dr. Shu-Ying Wang (王淑鶯老師) Place: Room 601

Abstract:

MDA5 is a viral double-stranded RNA (dsRNA) receptor which belongs to the RIG-I like receptor (RLR) family. Both MDA5 and RIG-I play an essential role in antiviral immunity; MDA5 shares similar sequence and signaling pathways with RIG-I, but MDA5 prefers recognizing longerdsRNA. The authors want to know the mechanism of how MDA5 recognize dsRNA by revealing the crystal structure of MDA5. Although MDA5 uses the same CTD (C-terminal domain) to bind dsRNA as RIG-I, MDA5 recognizes the internal duplex structure-whereas RIG-I recognizes the terminus of dsRNA. Moreover, the authors prove the helicase domain is important for ATP hydrolysis and subsequent signaling, and it can potentially serve as an additional mechanism to discriminate between dsRNA and other types of nucleic acids. The authors further show that MDA5 forms a filament by direct protein-protein interaction in a head-to-tail arrangement, and the N-terminal (CARD domain) of MDA5 decorates the outside of MDA5 filament. CARD has a propensity to self-oligomerize into an elongated structure which can activate a downstream mitochondrial adaptor, MAVS (or IPS-1). In conclusion, MDA5 uses long dsRNA as a signaling platform to assemble the MDA5 core filament, and the CARD oligomers form after that. The authors show three possible models of CARD oligomers in the MDA5 filament in the end of the article.

References:

1.      Peisley, A. et al. (2011) Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc. Natl. Acad. Sci. USA 108, 21010–21015.

2.      Peisley, A. et al. (2012) Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments. Proc. Natl. Acad. Sci. USA 109, E3340–E3349.

3.      Kowalinski, E. et al. (2011). Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell 147, 423–435.