期刊
MOLECULAR CELL
卷 72, 期 2, 页码 355-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.08.021
关键词
-
资金
- NIH [GM111959, GM118086]
- Intramural Research Program of NIAID
RIG-I has a remarkable ability to specifically select viral 5' ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient-state kinetics, we elucidated the ATPase-driven kinetic proofreading'' mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off rates. ATP binding facilitates dsRNA engagement but, interestingly, makes RIG-I promiscuous, explaining the constitutive signaling by Singleton-Merten syndrome-linked mutants that bind ATP without hydrolysis. ATP hydrolysis dissociates self-RNAs faster than 5' ppp dsRNA but, more importantly, drives RIG-I oligomerization through translocation, which we show to be regulated by helicase motif IVa. RIG-I translocates directionally from the dsRNA end into the stem region, and the 5' ppp end throttles'' translocation to provide a mechanism for threading and building a signaling-active oligomeric complex.
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