@article {6956, title = {Structural basis for the prion-like MAVS filaments in antiviral innate immunity.}, journal = {eLife}, volume = {3}, year = {2014}, month = {2014 Jan 1}, pages = {e01489}, abstract = {

Mitochondrial antiviral signaling (MAVS) protein is required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling cascades, but the underlying structural mechanism is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N-terminal caspase activation and recruitment domain (CARD) of MAVS and a truncated MAVS lacking part of the proline-rich region and the C-terminal transmembrane domain. Both structures are left-handed three-stranded helical filaments, revealing specific interfaces between individual CARD subunits that are dictated by electrostatic interactions between neighboring strands and hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments. DOI: http://dx.doi.org/10.7554/eLife.01489.001.

}, issn = {2050-084X}, doi = {10.7554/eLife.01489}, author = {Xu, Hui and He, Xiaojing and Zheng, Hui and Huang, Lily J and Hou, Fajian and Yu, Zhiheng and de la Cruz, Michael Jason and Borkowski, Brian and Zhang, Xuewu and Chen, Zhijian J and Jiang, Qiu-Xing} } @article {65045, title = {Voltage sensor ring in a native structure of a membrane-embedded potassium channel.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {110}, year = {2013}, month = {2013 Feb 26}, pages = {3369-74}, abstract = {

Voltage-gated ion channels support electrochemical activity in cells and are largely responsible for information flow throughout the nervous systems. The voltage sensor domains in these channels sense changes in transmembrane potential and control ion flux across membranes. The X-ray structures of a few voltage-gated ion channels in detergents have been determined and have revealed clear structural variations among their respective voltage sensor domains. More recent studies demonstrated that lipids around a voltage-gated channel could directly alter its conformational state in membrane. Because of these disparities, the structural basis for voltage sensing in native membranes remains elusive. Here, through electron-crystallographic analysis of membrane-embedded proteins, we present the detailed view of a voltage-gated potassium channel in its inactivated state. Contrary to all known structures of voltage-gated ion channels in detergents, our data revealed a unique conformation in which the four voltage sensor domains of a voltage-gated potassium channel from Aeropyrum pernix (KvAP) form a ring structure that completely surrounds the pore domain of the channel. Such a structure is named the voltage sensor ring. Our biochemical and electrophysiological studies support that the voltage sensor ring represents a physiological conformation. These data together suggest that lipids exert strong effects on the channel structure and that these effects may be changed upon membrane disruption. Our results have wide implications for lipid-protein interactions in general and for the mechanism of voltage sensing in particular.

}, keywords = {Aeropyrum, Cell Membrane, Cross-Linking Reagents, Crystallography, X-Ray, Electrons, Lipids, Models, Molecular, Potassium Channels, Voltage-Gated, Protein Structure, Secondary, Protein Structure, Tertiary}, issn = {1091-6490}, doi = {10.1073/pnas.1218203110}, author = {Shi, Liang and Zheng, Hongjin and Zheng, Hui and Borkowski, Brian A and Shi, Dan and Gonen, Tamir and Jiang, Qiu-Xing} } @article {4921, title = {The influence of lipids on voltage-gated ion channels.}, journal = {Current Opinion in Structural Biology}, volume = {22}, year = {2012}, month = {2012 Apr 5}, pages = {529-36}, abstract = {

Voltage-gated ion channels are responsible for transmitting electrochemical signals in both excitable and non-excitable cells. Structural studies of voltage-gated potassium and sodium channels by X-ray crystallography have revealed atomic details on their voltage-sensor domains (VSDs) and pore domains, and were put in context of disparate mechanistic views on the voltage-driven conformational changes in these proteins. Functional investigation of voltage-gated channels in membranes, however, showcased a mechanism of lipid-dependent gating for voltage-gated channels, suggesting that the lipids play an indispensible and critical role in the proper gating of many of these channels. Structure determination of membrane-embedded voltage-gated ion channels appears to be the next frontier in fully addressing the mechanism by which the VSDs control channel opening. Currently electron crystallography is the only structural biology method in which a membrane protein of interest is crystallized within a complete lipid-bilayer mimicking the native environment of a biological membrane. At a sufficiently high resolution, an electron crystallographic structure could reveal lipids, the channel and their mutual interactions at the atomic level. Electron crystallography is therefore a promising avenue toward understanding how lipids modulate channel activation through close association with the VSDs.

}, issn = {1879-033X}, doi = {10.1016/j.sbi.2012.03.009}, author = {Jiang, Qiu-Xing and Gonen, Tamir} }