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FEBS J. 2018 Jul;285(14):2579-2585. doi: 10.1111/febs.14443. Epub 2018 Apr 14.

The regulatory mechanism of mammalian TRPMLs revealed by cryo-EM.

Author information

1
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Abstract

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 (PH1 and PH2). 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-SA1, can bind to the pore region of TRPMLs 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 TRPMLs, 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 TRPMLs.

KEYWORDS:

PIP 2 ; TRPML ; ML-SA1; cryo-EM; pH regulation

PMID:
29577631
PMCID:
PMC6105560
[Available on 2019-07-01]
DOI:
10.1111/febs.14443

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