Mechanosensitive (MS) ion channels can sense and gate in response to mechanical forces, thus are able to convert the mechanical into electrical or chemical signals. MscK is the largest MscS-like MS channel, whose structure and function is unknown. In this project, we solved the structures of MscK in different conditions and conformational states by cryo-EM to intermediate resolution. These structures show that MscK features a curved transmembrane domain, which transits from curved to flat during its gating. The unique transmembrane domain we identified indicates that curvatures of the transmembrane domain and lipid membrane are conserved elements in the gating mechanism of this class of MS channels.
MscL is a well-studied MS channel, whose gating mechanism is still not clear because of the lack of its open state structure. Previously our group identified that bulk mutations of residue L89 could stabilize the MscL from Mycobacterium tuberculosis (TbMscL) in a sub-opened state. In this project, we performed MD simulations of TbMscL under different conditions and found that the sub-state is formed by blocking the lipids from penetrating hydrophobic pockets, which comes in support of the “lipid moves first” gating model according to which pocket delipidation is essential for MS channels to open.
Phosphatidylserine decarboxylase (PSD) is a conserved membrane anchoring enzyme that converts PS lipid to PE lipids. Particularly, in many bacteria PSD shares the operon with a member of MscS-like family MscM. To investigate the functional and structural relationship between PSD and MscM, we determined the high-resolution structure of PSD in nanodiscs by cryo-EM. We found that multiple PSD dimers can form ring shapes, indicating the native PSD complex should bind to locally curved (protruding) membrane, where MscM may also be localized, indicating PSD and MscM function in cooperation though spatial proximity.
