Abstract
The voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. Being associated with a variety of channelopathies, they are targeted by multiple pharmaceutical drugs and natural toxins. The speaker and her collaborator determined the crystal structure of a bacterial Nav channel NavRh in a potentially inactivated state a few years ago, which is a homotetramer in primary sequence but exhibits structural asymmetry. Employing the modern methods of cryo-EM, they determined the near atomic resolution structures of a Nav channel from American cockroach (designated NavPaS) and from electric eel (designated EeNav1.4). Most recently, they have determined the cryo-EM structures of the human Nav channels, Nav1.2, Nav1.4, and Nav1.7 in complex with distinct auxiliary subunits and toxins. These structures reveal the folding principle and structural details of the single-chain eukaryotic Nav channels that are distinct from homotetrameric voltage-gated ion channels. Unexpectedly, the two structures were captured in drastically different states. Whereas the structure of NavPaS has a closed pore and the four VSDs in distinct conformations, that of EeNav1.4 and the human channels is open at the intracellular gate with VSDs exhibiting similar “up” states. The most striking conformational difference occurs to the III-IV linker, which is essential for fast inactivation. Based on the structural features, they suggest an allosteric blocking mechanism for fast inactivation of Nav channels by the IFM motif. Structural comparison of the conformationally distinct Nav channels provides important insights into the electromechanical coupling mechanism of Nav channels and offers the 3D template to map hundreds of disease mutations.
About the speaker
Prof. Yan Nieng received her BS from the Department of Biological Sciences & Biotechnology, Tsinghua University in 2000. She then pursued her PhD in Molecular Biology at Princeton University between 2000 and 2004. In 2007, she joined the School of Medicine of Tsinghua University as a Principal Investigator and eventually became the Bayer Professor. She returned to Princeton University in 2017 and is currently the Shirley M. Tilghman Professor of Molecular Biology.
Prof. Yan’s research aims to reveal the molecular choreography at atomic resolution, as well as to unveil the physiological and cellular processes involving membrane transport (including cellular uptake of glucose, generation of action potential, and excitation-contraction coupling of muscles).
Prof. Yan received numerous awards including the Weizmann Women & Science Award by the Weizmann Institute of Science (2019); the Award for Research Excellence by the Federation of Asian and Oceanian Biochemists and Molecular Biologists (2018) and the Protein Science Young Investigator Award by the Protein Society (2015). She was also elected the Howard Hughes Medical Institute International Early Career Scientist during 2012-2017.
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