TY - JOUR
T1 - Structural basis for PtdInsP2-mediated human TRPML1 regulation
AU - Fine, Michael
AU - Schmiege, Philip
AU - Li, Xiaochun
N1 - Funding Information:
This research was done in the memory of G. Blobel for his generosity and encouragement. The data were collected at the UT Southwestern Medical Center Cryo-EM Facility (funded in part by the CPRIT Core Facility Support Award RP170644); we thank D. Nicastro for the access of cryo-EM, and Z.G. Chen and D. Stoddard for assistance in data collection. We thank Z.X. Chen, D. Hilgemann, E. Coutavas, and E. Debler for help in manuscript preparation. M.F. wishes to thank S. Lin for years of support. This work was supported by the Endowed Scholars Program in Medical Science of UT Southwestern Medical Center and O’Donnell Junior Faculty Funds (to X.L.) and NIH grant P01 HL020948 (Tissue Culture Core); X.L. is Rita C. and William P. Clements, Jr. Scholar in Biomedical Research of UT Southwestern.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a π-cation interaction with R403, moving the S4–S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.
AB - Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a π-cation interaction with R403, moving the S4–S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.
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U2 - 10.1038/s41467-018-06493-7
DO - 10.1038/s41467-018-06493-7
M3 - Article
C2 - 30305615
AN - SCOPUS:85054732457
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4192
ER -