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

Bin Wu; Alys Peisley; David Tetrault; Zongli Li; Edward H Egelman; Katharine E Magor; Thomas Walz; Pawel A Penczek; Sun Hur

doi:10.1016/j.molcel.2014.06.010

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.

Authors

Bin Wu¹, Alys Peisley¹, David Tetrault², Zongli Li³, Edward H Egelman⁴, Katharine E Magor², Thomas Walz³, Pawel A Penczek⁵, Sun Hur⁶

Affiliations

¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
² Department of Biological Sciences and the Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E9, Canada.
³ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁴ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
⁵ Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
⁶ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA. Electronic address: sun.hur@childrens.harvard.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding