期刊
STRUCTURE
卷 20, 期 12, 页码 2048-2061出版社
CELL PRESS
DOI: 10.1016/j.str.2012.09.003
关键词
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资金
- UTE project CIMA [JCI-2011-09179]
- Ministerio de Ciencia e Innovacion [SAF2009-08524]
- NIAID [U19AI083025]
- NYSTAR
- ORIP/NIH [CO6RR015495]
- NIH [P41GM066354]
- Keck Foundation, New York State
- NYC Economic Development Corporation
RIG-I is a cytosolic sensor of viral RNA, comprised of two N-terminal CARDs followed by helicase and C-terminal regulatory domains (helicase-CTD). Viral RNA binds to the helicase-CTD and exposes the CARDs for downstream signaling. The role of the second CARD (CARD2) is essential as RIG-I activation requires dephosphorylation of Thr170 followed by ubiquitination at Lys172. Here, we present the solution structure and dynamics of human RIG-I CARD2. Surprisingly, we find that Thr170 is mostly buried. Parallel studies on the phosphomimetic T170E mutant suggest that the loss of function upon Thr170 phosphorylation is likely associated with changes in the CARD1-CARD2 interface that may prevent Lys172 ubiquitination and/or binding to free K63-linked polyubiquitin. We also demonstrate a strong interaction between CARD2 and the helicase-CTD, and show that mutations at the interface result in constitutive activation of RIG-I. Collectively, our data suggests a close interplay between phosphorylation, ubiquitination, and activation of human RIG-I, all mediated by CARD2.
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