The regulatory mechanism of mammalian TRPMLs revealed by cryo-EM

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • Gene Expression
  • Humans
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / metabolism
  • Lysosomal Storage Diseases / pathology
  • Lysosomes / chemistry
  • Lysosomes / metabolism
  • Models, Molecular
  • Phosphatidylinositol Phosphates / chemistry*
  • Phosphatidylinositol Phosphates / metabolism
  • Phthalimides / chemistry*
  • Phthalimides / metabolism
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Quinolines / chemistry*
  • Quinolines / metabolism
  • TRPV Cation Channels / chemistry*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Transient Receptor Potential Channels / agonists
  • Transient Receptor Potential Channels / chemistry*
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / metabolism


  • MCOLN1 protein, human
  • MCOLN3 protein, human
  • ML-SA1 compound
  • Phosphatidylinositol Phosphates
  • Phthalimides
  • Quinolines
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Transient Receptor Potential Channels
  • phosphatidylinositol 3,5-diphosphate

Associated data

  • PDB/5W3S
  • PDB/5JW9
  • PDB/5IRX
  • PDB/5KLG