Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG-I

Mol Cell. 2014 Aug 21;55(4):511-23. doi: 10.1016/j.molcel.2014.06.010. Epub 2014 Jul 10.

Abstract

RIG-I activates interferon signaling pathways by promoting filament formation of the adaptor molecule, MAVS. Assembly of the MAVS filament is mediated by its CARD domain (CARD(MAVS)), and requires its interaction with the tandem CARDs of RIG-I (2CARD(RIG-I)). However, the precise nature of the interaction between 2CARD(RIG-I) and CARD(MAVS), and how this interaction leads to CARD(MAVS) filament assembly, has been unclear. Here we report a 3.6 Å electron microscopy structure of the CARD(MAVS) filament and a 3.4 Å crystal structure of the 2CARD(RIG-I):CARD(MAVS) complex, representing 2CARD(RIG-I) "caught in the act" of nucleating the CARD(MAVS) filament. These structures, together with functional analyses, show that 2CARD(RIG-I) acts as a template for the CARD(MAVS) filament assembly, by forming a helical tetrameric structure and recruiting CARD(MAVS) along its helical trajectory. Our work thus reveals that signal activation by RIG-I occurs by imprinting its helical assembly architecture on MAVS, a previously uncharacterized mechanism of signal transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites / physiology*
  • DEAD-box RNA Helicases / chemistry*
  • DEAD-box RNA Helicases / metabolism
  • Microscopy, Electron
  • Models, Molecular
  • Molecular Imprinting / methods*
  • Protein Conformation
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • RNA, Viral / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • RNA, Viral
  • DEAD-box RNA Helicases