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Structural insights into RNA recognition and activation of RIG-I-like receptors - PubMed

Review

Structural insights into RNA recognition and activation of RIG-I-like receptors

Daisy W Leung et al. Curr Opin Struct Biol. 2012 Jun.

Abstract

RIG-I like receptors (RLR) that recognize non-self RNA play critical roles in activating host innate immune pathways in response to viral infections. Not surprisingly, RLRs and their associated signaling networks are also targeted by numerous antagonists that facilitate viral pathogenesis. Although the role of RLRs in orchestrating antiviral signaling has been recognized for some time, our knowledge of the complex regulatory mechanisms that control signaling through these key molecules is incomplete. A series of recent structural studies shed new light into the structural basis for dsRNA recognition and activation of RLRs. Collectively, these studies suggest that the repression of RLRs is facilitated by a cis element that makes multiple contacts with domains within the helicase and that RNA binding initiated by the C-terminal RNA binding domain is important for ATP hydrolysis and release of the CARD domain containing signaling module from the repressed conformation. These studies also highlight potential differences between RIG-I and MDA5, two RLR members. Together with previous studies, these new results bring us a step closer to uncovering the complex regulatory process of a key protein that protects host cells from invading pathogens.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Figures

Figure 1
Figure 1

Domain architecture of RIG-I-like receptors. RIG-I and MDA-5 have similar domain organization. The domains are: CARD1 (cyan), CARD2 (blue), helicase HEL1 (green), helicase insertion domain HEL2i (yellow), helicase HEL2 (purple), the regulatory pincer motif P (red), and C-terminal domain CTD (orange). LGP2 lacks the N-terminal CARDs.

Figure 2
Figure 2

Structural basis for dsRNA recognition and activation of RLRs. (a) C-terminal RNA binding domain in the presence of RNA (PDB: 3NCU). (b) Helicase domain in the presence of RNA (PDB: 4A36). (c) In the autoinhibited conformation, the N-terminal CARDs are sequestered from signaling and the pincer maintains RIG-I in an autoinhibited state (PDB: 4A2W). Binding of dsRNA to the CTD brings HEL2i in contact with dsRNA (PDB: 2YKG). The change in conformation upon dsRNA binding presumably releases the CARD domains for signaling.

Figure 3
Figure 3

A structure based model dsRNA-mediated RLR regulation and signaling. (a) Functional elements in RLRs. The CARD domains comprise the signaling region, the helicase serves as the activation domain, the pincer is the regulatory element, and the C-terminal domain is the RNA binding domain. (b) Schematic model of the activation mechanism in RIG-I. In the absence of dsRNA, RIG-I exists in an autoinhibited conformation that is regulated by the pincer motif, which prevents the N-terminal CARDs from signaling. Binding of dsRNA to the CTD relieves repression by the pincer motif, initiates dsRNA binding to HEL2i, and releases the CARDs from HEL2i to become polyubiquinated and activate production of Type I IFNs.

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