TY - JOUR
T1 - Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P2 and rapamycin
AU - Gan, Ninghai
AU - Han, Yan
AU - Zeng, Weizhong
AU - Wang, Yan
AU - Xue, Jing
AU - Jiang, Youxing
N1 - Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/2/15
Y1 - 2022/2/15
N2 - 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.
AB - 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.
KW - Lysosomal channel
KW - PI(3,5)P2
KW - Rapamycin
KW - TRPML1
UR - http://www.scopus.com/inward/record.url?scp=85124254875&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124254875&partnerID=8YFLogxK
U2 - 10.1073/pnas.2120404119
DO - 10.1073/pnas.2120404119
M3 - Article
C2 - 35131932
AN - SCOPUS:85124254875
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
M1 - e2120404119
ER -