Molecular Mechanism of TRPV2 Channel Pore Dynamics during Ligand Activation

Abstract

The transient receptor potential (TRP) superfamily, one of the largest families of the non-selective cation channels, is subdivided into six major branches: TRPV, TRPC, TRPM, TRPA, TRPP, and TRPML. The TRPV subfamily contains six unique members, four non-selective cation channels (TRPV1-TRPV4) and two highly Ca2+ selective channels (TRPV5 and TRPV6). A hallmark of these polymodal TRP channels is their exceptionally high permeability to large organic cations in response to prolonged ligand stimulation. The pore dilation phenomenon has been proposed to play a role in this process. Although cryo-electron microscopy structures of various TRP channels have been resolved in both apo and ligand bound states, the structural basis of this uptake is unknown due to unavailability of the full-length TRP structures in ligand-activated states. Recent cryo-electron microscopy (cryo-EM) structure of full-length rat TRPV2 in the apo state revealed details about TRPV2 channel architecture, but did not elucidate aspects of channel activation and gating. We have determined a ligand-activated TRPV2 structure, which displayed a distinct channel gating mechanism that involves rearrangement of the S5 helix, pore turret and selectivity filter domains. Together these results provide foundation to further understanding TRP channels large organic cations’ permeation, their gating properties and divergent physiological functions.