Characterizing the lipid fingerprint of the mechanosensitive channel Piezo2

Piezo2 is a membrane protein that activates in response to mechanical signals and plays key roles in humans. Lipids in the membrane such as cholesterol and phosphoinositides modulate Piezo2's function. We used computational simulations of Piezo2 in a realistic mammalian membrane to investigate how lipids interact with Piezo2. Piezo2 is a mechanosensitive ion channel that plays critical roles in sensing touch and pain, proprioception, and regulation of heart rate. Global knockout of Piezo2 leads to perinatal lethality in mice, and Piezo2 gain-of-function mutations are associated with distal arthrogryposis, a disease characterized by congenital joint contractures. Emerging evidence suggests that Piezo channels (Piezo1 and Piezo2) can be regulated by their local membrane environment and particularly by cholesterol and phosphoinositides. To characterize the local Piezo2 lipid environment and investigate key lipid-protein interactions, we carried out coarse-grained molecular dynamics simulations of Piezo2 embedded in a complex mammalian membrane containing >60 distinct lipid species. We show that Piezo2 alters its local membrane composition such that it becomes enriched with specific lipids, such as phosphoinositides, and forms specific, long-term interactions with a variety of lipids at functionally relevant sites.