Molecular dynamics simulations reveal the activation mechanism of human TMEM63A induced by lysophosphatidylcholine insertion

OSCA/TMEM63 protein families are recognized as typical mechanosensitive (MS) ion channels in both plants and animals. Resolved OSCA and TMEM63 structures have revealed that these channels are forming dimer and monomer, respectively. Despite the distinguished architectures, OSCA and TMEM63 serve similar functions in multiple physiological processes. Recently, human TMEM63A (hTMEM63A) structure was identified, allowing for investigation into the activation mechanism of hTMEM63A through molecular dynamics (MD) simulations. In this study, we performed multi-scale MD simulations toward hTMEM63A, aiming to reveal how lipid binding regulates hTMEM63A activation. Our results identified two regions on the surface of hTMEM63A, exhibiting a preference for lysophosphatidylcholine (LPC) lipids. Further conformation analyses clarified the activation mechanism of hTMEM63A induced by LPC insertion. These simulation results provide detailed insights into the hTMEM63A–lipid interaction and significant conformational changes associated with hTMEM63A gating, thereby shed lights on the MS ion channel activation mechanism driven by lipid plugging.