The Department of Biological Sciences is pleased to announce that the 2018 Schuetze lecture will be delivered on April 30th, 2018 by Dr. Nieng Yan, the Shirley J. Tilghman Professor of Molecular Biology at Princeton University.
Host: Jian Yang
Title: How is electrical signal generated? Structural and mechanistic investigations of Nav channels
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. We 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, we recently determined the near atomic resolution structures of a Nav channel from American cockroach (designated NavPaS) and from electric eel (designated EeNav1.4). 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 four VSDs in distinct conformations, that of EeNav1.4 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. The III-IV undergoes a pronounced repositioning from NavPaS to EeNav1.4, resulting in the insertion of the IFM fast inactivation motif on the III-IV linker into the corner enclosed by the S4-S5 and S6 segments in repeats III and IV of EeNav1.4. Based on the structural features, we suggest an allosteric blocking mechanism for fast inactivation of Nav channels by the IFM motif. Structural comparison of the conformationally distinct EeNav1.4 and NavPaS provides important insights into the electromechanical coupling mechanism of Nav channels.
About Dr. Yan: Dr. Nieng Yan received her B.S. degree from the Department of Biological Sciences & Biotechnology, Tsinghua University, Beijing, China, in 2000. She then pursued her PhD in the Department of Molecular Biology at Princeton University under the supervision of Prof. Yigong Shi between 2000 and 2004. She was the regional winner of the Young Scientist Award (North America) co-sponsored by Science/AAAS and GE Healthcare in 2005 for her thesis on the structural and mechanistic study of programmed cell death. She continued her postdoctoral training at Princeton University, focusing on the structural characterization of intramembrane proteases. In 2007, she joined the faculty of School of Medicine, Tsinghua University. Her lab has been mainly focusing on the structural and functional study of membrane transport proteins exemplified by the glucose transporters and Nav/Cav channels. In 2012 and 2013, she was promoted to tenured professor and Bayer Endowed Chair Professor, respectively. She returned to Princeton University as the founding Shirley M. Tilghman Professor of Molecular Biology in 2017. Dr. Yan was an HHMI international early career scientist in 2012-2017, Cheung Kong Scholar, the recipient of the 2015 Protein Society Young Investigator Award, the 2015 Beverley & Raymond Sackler International Prize in Biophysics, the Alexander M. Cruickshank Award at the GRC on membrane transport proteins in 2016, and the 2018 FAOBMB Award for Research Excellence.