The molecular basis of force selectivity by PIEZO2

Area of Science:

• Biophysics
• Cell Biology
• Neuroscience

Background:

• PIEZO channels are mechanosensitive ion channels that convert mechanical force into cellular signals.
• PIEZO1 and PIEZO2 exhibit distinct stimulus selectivities, with PIEZO2 implicated in touch sensation.
• The molecular mechanisms underlying PIEZO2's specialized mechanosensing remain unclear.

Purpose of the Study:

• To elucidate the structural and mechanical properties that confer PIEZO2 its specialized function.
• To link PIEZO2's conformational states to its gating mechanisms in response to mechanical stimuli.
• To identify molecular interactions that mediate PIEZO2's selective response to cellular indentation.

Main Methods:

• Single-molecule MINFLUX fluorescence nanoscopy
• Electrophysiology in intact cells
• Identification of interacting proteins via molecular tethering assays

Main Results:

• PIEZO2 is intrinsically more rigid than PIEZO1.
• Mechanical stimuli induce opposite conformational and gating responses in PIEZO1 and PIEZO2.
• Filamin-B (FLNB) tethers PIEZO2 to the actin cytoskeleton, enhancing sensitivity to indentation.
• PIEZO2 and FLNB colocalize in somatosensory neurons.

Conclusions:

• PIEZO2's rigidity and interaction with the actin cytoskeleton via FLNB explain its specialized role in mechanotransduction.
• These findings provide a molecular basis for PIEZO2's selective detection of cellular indentation.
• The study offers insights into how cells decode mechanical signals for physiological functions.