Poster abstracts
Poster number 13 submitted by Rupam Biswas
Structural insights into the cardiac voltage-gated sodium channel Nav1.5
Rupam Biswas (PhD), Isabelle Deschenes (PhD), Krishna Chinthalapudi (PhD)
Abstract:
Voltage-gated sodium channels are essential for excitable cells such as neurons and cardiac muscle cells. Nav1.5, also known as the cardiac voltage-gated sodium channel initiates cardiac action potential. Nav1.5 opens quickly, allowing a rapid influx of Na+ ions. Then it shifts to fast inactivation state within few milliseconds. However, the structural basis for pore opening in human full-length Nav1.5, as well as the conformation of the C-terminal domain (CTD), remain unknown. Furthermore, the molecular mechanism underlying the switch from open-state to fast inactivation state, as well as CTD-based regulation, remains obscure. Here we present three open-state cryo-EM structures of human Nav1.5 at global resolution range from ~ 3.2 Å to ~ 3.6 Å. The overall structure is dilated, resulting in the open-state conformation of the activation gate. We found that the tilting of the S0 helix of Domain-IV (DIV) and the repositioning of IFM motif are coupled with an interaction between the dynamic CTD and the III-IV linker. This interaction regulates the conformation of the voltage-sensing domains (VSDs) and stabilizes the open-state of the activation gate. Together, these structures provide previously unanticipated conformational snapshots of the kinetic cycle of Nav1.5 and establish a foundation for understanding the gating mechanisms of Nav1.5.
References:
1. D. Jiang et al., Structure of the Cardiac Sodium Channel. Cell 180, 122-134 e110 (2020).
2. D. Jiang et al., Open-state structure and pore gating mechanism of the cardiac sodium channel. Cell 184, 5151-5162 e5111 (2021).
3. Z. Li et al., Structure of human Na(v)1.5 reveals the fast inactivation-related segments as a mutational hotspot for the long QT syndrome. Proc Natl Acad Sci U S A 118, (2021).
Keywords: Voltage-gated sodium channel, Open-state, Cryo-EM