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

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

doi:10.1073/pnas.2120404119

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

Journal Article · 06 February 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.2120404119 · OSTI ID:1903936

Gan, Ninghai ^[1];

^[2]; Zeng, Weizhong ^[2]; Wang, Yan ^[2]; Xue, Jing ^[2];

^[2]

University of Texas Southwestern Medical Center, Dallas, TX (United States); OSTI
University of Texas Southwestern Medical Center, Dallas, TX (United States)

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 small-molecule 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.

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Research Organization:: University of Texas Southwestern Medical Center, Dallas, TX (United States)

Sponsoring Organization:: Cancer Prevention and Research Institute of Texas; Howard Hughes Medical Institute (HHMI); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER); Welch Foundation

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1903936

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 7 Vol. 119; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
PI(3
5)P2
TRPML1
lysosomal channel
rapamycin

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

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