Open AccessStructural mechanism of allosteric activation of TRPML1 by PI(3,5)P 2 and rapamycin
Author(s) -
Ninghai Gan,
Yanping Han,
Weizhong Zeng,
Yan Wang,
Jing Xue,
Youxing Jiang
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2120404119
Subject(s) - allosteric regulation , transient receptor potential channel , biophysics , ligand (biochemistry) , chemistry , biology , biochemistry , microbiology and biotechnology , receptor
Significance Rapamycin is a specific inhibitor of mammalian target of rapamycin (mTOR). Rapamycin can also activate transient receptor potential mucolipin 1 (TRPML1), a phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2 ]–gated lysosomal cation channel whose loss-of-function mutations directly cause mucolipidosis type IV disease. We determined the high-resolution cryoelectron microscopy structures of TRPML1 in various ligand-bound states, including the open TRPML1 in complex with PI(3,5)P2 and a rapamycin analog at 2.1 Å. These structures reveal how rapamycin and PI(3,5)P2 bind at two distinct sites and allosterically activate the channel. Considering the high potency of TRPML1 activation by rapamycin and PI(3,5)P2 , it is conceivable that some pharmacological effects from the therapeutic use of rapamycin may come from the TRPML1-dependent mechanism rather than mTOR inhibition.