Mechanical force signals are involved in mediating the formation of various perceptual senses. The perception and transmission of these mechanical force signals are mainly achieved through mechanical force sensitive ion channels. Mechanical force signals can activate these channels, allowing ions to pass through, converting mechanical force signals into electrochemical signals, and mediating various physiological activities through downstream signal transduction. At present, the OSCA/TMEM63 family is the largest known mechanical force sensitive ion channel family, responsible for important physiological functions in both plant and animal kingdoms, such as stress response, hearing, thirst, and humidity perception. However, simulating the mechanical force environment during structural analysis is very difficult, so the molecular mechanism of mechanical force activation of OSCA/TMEM63 family proteins is not yet clear.

On April 3, Zhang Yixiao's research group from the Biology and Chemistry Cross Research Center of the Chinese Academy of Sciences Shanghai Institute of Organic Chemistry and the National Key Laboratory of Small Molecule Regulation in Life Processes, together with Charles Cox's research group from the Australian Zhang Renqian Heart Research Institute and Ben Corry's research group from the Australian National University, published a research article entitled Mechanical activation opens a lipid lined point in OSCA ion channels in Nature. This study assembled OSCA protein into nano phospholipid discs and liposomes to simulate a mechanical force environment, captured the three-dimensional conformation of OSCA protein activation state, elucidated its molecular mechanism of mechanical force activation, and discovered a novel form of "protein phospholipid" ion pore composition. This provides a new paradigm for the study of mechanical force channels and lays a theoretical and structural foundation for the development of drugs related to mechanical force perception abnormalities.

This study uses multiple strategies to capture the three-dimensional conformation of OSCA protein activation states; A simple and easy-to-use mechanical force simulation method for lipid titration has been developed using nano phospholipid discs to conduct structural research on mechanical force resolution; High resolution three-dimensional structural analysis of membrane proteins with molecular weight less than 200kDa in liposomes has been achieved; Revealed the role of different phospholipids in OSCA mechanical force perception process; It has been discovered that phospholipids in cell membranes can participate in the composition of ion channels by forming lipid walls through their lipid heads.

The OSCA/TMEM63 family proteins have a high degree of structural similarity with the TMC1 mechanosensitive channel mediated by auditory formation, as well as the TMEM16 family proteins with ion channel and lipid flipping enzyme activity. This provides inspiration for the molecular mechanism research of structurally similar family proteins. In addition, this study developed a new mechanical force environment simulation method based on nano phospholipid discs, expanding the feasibility of structural analysis of small membrane proteins in liposomes, and providing new ideas for the study of other membrane proteins, including mechanical force channels.

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