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The regulatory mechanism of mammalian TRPML s revealed by cryo‐ EM
Author(s) -
Schmiege Philip,
Fine Michael,
Li Xiaochun
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14443
Subject(s) - transient receptor potential channel , subfamily , biophysics , trpv , chemistry , agonist , transmembrane domain , transmembrane protein , linker , microbiology and biotechnology , biochemistry , biology , receptor , gene , trpv1 , computer science , operating system
Transient receptor potential mucolipin ( TRPML ) channels are the most recently identified subfamily of TRP channels and have seen a surge of new reports revealing both structural and functional insight. In 2017, several groups published multiple conformations of TRPML channels using cryo‐ EM . Similar to other TRP channels, the ML subfamily consists of six transmembrane helices (S1–S6), and a pore region including S5, S6, and two pore helices ( PH 1 and PH 2). However, these reports also reveal distinct structural characteristics of the ML subfamily. Asp residues within the luminal pore may function to control calcium/ pH regulation. A synthetic agonist, ML ‐ SA 1, can bind to the pore region of TRPML s to force a direct dilation of the lower gate. Finally, biophysical and electrophysiological characterizations reveal another natural agonist binding site in the unique domain of TRPML s, presumably regulating the conformation of the S4–S5 linker to open the channel. This work elucidates the molecular architecture and provides insights into how multiple ligands regulate TRPML s.