A two-step clockwork mechanism opens a proteo-lipidic pore in PIEZO2

Area of Science:

• Biophysics
• Molecular Biology
• Structural Biology

Background:

• Mechanosensitive PIEZO channels are crucial for cellular mechanotransduction.
• The precise structural mechanism of PIEZO channel gating remains largely unknown.
• PIEZO2 channels are implicated in various physiological processes, including touch and proprioception.

Purpose of the Study:

• To elucidate the structural basis of PIEZO2 channel activation under physiological tension.
• To understand how large-scale domain movements translate into pore gating.
• To investigate the role of lipids and protein structures in PIEZO2 channel function.

Main Methods:

• Hybrid-resolution molecular dynamics simulations were employed to model PIEZO2 channel dynamics.
• Electrophysiological recordings were used to validate simulation findings.
• Analysis of large-scale arm movements and pore domain motions.

Main Results:

• PIEZO2 channel gating involves a two-step mechanism driven by tension-induced arm flattening.
• Arm flattening leads to pore rotation and inner helix twisting, opening the channel.
• A stable subconducting state was identified at low tension.
• The fully open pore is lined by lipids and amino acids, matching experimental conductance and selectivity.

Conclusions:

• The study reveals a detailed "clockwork" mechanism for PIEZO2 channel gating.
• Hybrid-resolution simulations provide powerful insights into membrane protein dynamics.
• Findings advance our understanding of mechanosensation and may guide drug discovery for PIEZO channelopathies.