Research School of Biology, Canberra, Australia.
J Gen Physiol. 2022 Oct 3;154(10). doi: 10.1085/jgp.202113064. Epub 2022 Jul 21.
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.
Piezo2 是一种机械敏感离子通道，在触觉和疼痛感知、本体感觉以及心率调节中发挥着关键作用。Piezo2 的全球敲除会导致小鼠围产期致死，而 Piezo2 的功能获得性突变与远端关节挛缩症有关，这种疾病的特征是先天性关节挛缩。新出现的证据表明，Piezo 通道（Piezo1 和 Piezo2）可以通过其局部膜环境，特别是胆固醇和磷酸肌醇来调节。为了描述 Piezo2 的局部脂质环境并研究关键的脂质-蛋白相互作用，我们对嵌入含有 >60 种不同脂质的复杂哺乳动物膜中的 Piezo2 进行了粗粒分子动力学模拟。我们表明，Piezo2 改变了其局部膜组成，使其富含特定的脂质，如磷酸肌醇，并在功能相关位点与各种脂质形成特定的、长期的相互作用。
