Special Seminar – Dr. Charles Cox, Victor Chang Cardiac Research Institute, Australia

Discovery and characterization of a novel family of PIEZO channel auxiliary subunits

PIEZO channels are critical cellular sensors of mechanical forces. Native PIEZO1 channels can display nonuniform subcellular localization and exhibit different gating kinetics—principally, slower inactivation in many cell types when compared with heterologous expression systems. These observations could be explained by differences in lipid composition, curvature-dependent sorting or protein-protein interactions. Despite their large size, ubiquitous expression, and irreplaceable roles in an ever-growing list of physiological processes, few PIEZO channel-binding proteins have emerged. Recently using affinity capture mass spectrometry in conjunction with fibroblast cell lines edited using CRISPR/Cas9 we found that MyoD family inhibitor proteins (MDFIC and MDFI), interact with both PIEZO1 and PIEZO2 channels. We confirmed using co-immunoprecipitation that these transcriptional regulators, bind to PIEZO1/2 channels and patch-clamp electrophysiology revealed they regulate channel inactivation. Using single-particle cryo-electron microscopy, we mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These PIEZO interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous PIEZO channels observed in many cell types, shine light on mechanisms potentially involved in human lymphatic vascular disease and pave the way for novel mechano-signaling pathways directly linking PIEZO channels to transcription.

Location: CCB-3217

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