Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P2 and rapamycin

Ninghai Gan, Yan Han, Weizhong Zeng, Yan Wang, Jing Xue, Youxing Jiang

Research output: Contribution to journalArticlepeer-review

Abstract

Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] as well as some synthetic smallmolecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P2 and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P2 and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo- EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P2-bound closed, and PI(3,5)P2/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.

Original languageEnglish (US)
Article numbere2120404119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number7
DOIs
StatePublished - Feb 15 2022
Externally publishedYes

Keywords

  • Lysosomal channel
  • PI(3,5)P2
  • Rapamycin
  • TRPML1

ASJC Scopus subject areas

  • General

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