Regulatory switch at the cytoplasmic interface controls TRPV channel gating

Area of Science:

• Molecular Biology
• Structural Biology
• Biophysics

Background:

• Temperature-sensitive transient receptor potential vanilloid (thermoTRPV) channels are crucial for physiological processes, activated by heat and ligands.
• These channels feature a large cytoplasmic ring, comprising N-terminal ankyrin repeat domains (ARD) and C-terminal domains (CTD).
• The unique cytoplasmic inter-protomer interface, with CTD coiled around a β-sheet contacting ARD, is implicated in function, but its gating mechanism remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which the cytoplasmic ring structure of thermoTRPV channels, specifically TRPV3, is involved in channel gating.
• To investigate the role of the cytoplasmic inter-protomer interface in thermoTRPV channel function and subtype-specific properties.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine high-resolution structures.
• Electrophysiological studies to assess channel activity and gating mechanisms.
• Structural and functional analysis of the cytoplasmic ring and inter-protomer interface.

Main Results:

• Cryo-EM and electrophysiology reveal that TRPV3 gating involves significant rearrangements at the cytoplasmic inter-protomer interface.
• These rearrangements trigger coupling between cytoplasmic and transmembrane domains, initiating the channel opening process.
• The study identifies the critical role of this interface in conferring distinct biophysical and physiological properties to different thermoTRPV subtypes.

Conclusions:

• The cytoplasmic inter-protomer interface is a key regulatory site for thermoTRPV channel gating.
• Structural rearrangements at this interface are essential for coupling thermal and ligand stimuli to channel opening.
• Understanding this interface provides insights into the diverse functions and properties of thermoTRPV channels.