The intrinsically disordered CARDs-Helicase linker in RIG-I is a molecular gate for RNA proofreading.

Autor: Schweibenz BD; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.; Graduate Program in Biochemistry, Rutgers University, Piscataway, NJ, USA., Devarkar SC; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.; Graduate Program in Biochemistry, Rutgers University, Piscataway, NJ, USA., Solotchi M; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.; Cell and Development Biology, Rutgers University, Piscataway, NJ, USA., Craig C; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.; Graduate Program in Biochemistry, Rutgers University, Piscataway, NJ, USA., Zheng J; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Pascal BD; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Gokhale S; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA.; Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, USA., Xie P; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA.; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA., Griffin PR; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.; Department of Integrative Structural and Computational Biology, Jupiter, FL, USA., Patel SS; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2022 May 16; Vol. 41 (10), pp. e109782. Date of Electronic Publication: 2022 Apr 19.
DOI: 10.15252/embj.2021109782
Abstrakt: The innate immune receptor RIG-I provides a first line of defense against viral infections. Viral RNAs are recognized by RIG-I's C-terminal domain (CTD), but the RNA must engage the helicase domain to release the signaling CARD (Caspase Activation and Recruitment Domain) domains from their autoinhibitory CARD2:Hel2i interactions. Because the helicase itself lacks RNA specificity, mechanisms to proofread RNAs entering the helicase domain must exist. Although such mechanisms would be crucial in preventing aberrant immune responses by non-specific RNAs, they remain largely uncharacterized to date. This study reveals a previously unknown proofreading mechanism through which RIG-I ensures that the helicase engages RNAs explicitly recognized by the CTD. A crucial part of this mechanism involves the intrinsically disordered CARDs-Helicase Linker (CHL), which connects the CARDs to the helicase subdomain Hel1. CHL uses its negatively charged regions to antagonize incoming RNAs electrostatically. In addition to this RNA gating function, CHL is essential for stabilization of the CARD2:Hel2i interface. Overall, we uncover that the CHL and CARD2:Hel2i interface work together to establish a tunable gating mechanism that allows CTD-chosen RNAs to bind the helicase domain, while at the same time blocking non-specific RNAs. These findings also indicate that CHL could represent a novel target for RIG-I-based therapeutics.
(© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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