{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Schmiege P"],"funding":["U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences","U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)","NHLBI NIH HHS","U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute","G. Harold and Leila Y. Mathers Foundation","Welch Foundation","G. Harold and Leila Y. Mathers Foundation (G. Harold & Leila Y. Mathers Foundation)","U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)","NIGMS NIH HHS"],"pagination":["5325"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12174366"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(1)"],"pubmed_abstract":["TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular mechanism underlying this unique isomeric preference as well as the TRPML2 agonistic mechanism remains unknown. Here, we present six cryo-EM structures of human TRPML2 in distinct states revealing that the π-bulge of the S6 undergoes a π-α transition upon agonist binding, highlighting the remarkable role of the π-bulge in ion channel regulation. Moreover, we identify that PI(3,5)P<sub>2</sub> allosterically affects the pose of ML2-SA1, a TRPML2 specific activator, resulting in an open channel without the π-α transition. Functional and structural studies show that mutating the S5 of TRPML1 to that of TRPML2 enables the mutated TRPML1 to be activated by (+)ML-SI3 and ML2-SA1. Thus, our work elucidates the activation mechanism of TRPML channels and paves the way for the development of selective TRPML modulators."],"journal":["Nature communications"],"pubmed_title":["TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family."],"pmcid":["PMC12174366"],"funding_grant_id":["R35 GM149533","MF-2302-03702","P01HL160487","R35GM149533","I-1957","P01 HL020948"],"pubmed_authors":["Hatton A","Jaslan D","Li X","Sadanandan NP","Fine M","Elghobashi-Meinhardt N","Schmiege P","Grimm C"],"additional_accession":[]},"is_claimable":false,"name":"TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family.","description":"TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular mechanism underlying this unique isomeric preference as well as the TRPML2 agonistic mechanism remains unknown. Here, we present six cryo-EM structures of human TRPML2 in distinct states revealing that the π-bulge of the S6 undergoes a π-α transition upon agonist binding, highlighting the remarkable role of the π-bulge in ion channel regulation. Moreover, we identify that PI(3,5)P<sub>2</sub> allosterically affects the pose of ML2-SA1, a TRPML2 specific activator, resulting in an open channel without the π-α transition. Functional and structural studies show that mutating the S5 of TRPML1 to that of TRPML2 enables the mutated TRPML1 to be activated by (+)ML-SI3 and ML2-SA1. Thus, our work elucidates the activation mechanism of TRPML channels and paves the way for the development of selective TRPML modulators.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Jun","modification":"2026-06-03T07:55:22.556Z","creation":"2026-04-26T03:10:41.392Z"},"accession":"S-EPMC12174366","cross_references":{"pubmed":["40527873"],"doi":["10.1038/s41467-025-60710-8"]}}