TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family
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.
Authors
- Christian Grimm (ORCID: https://orcid.org/0000-0002-0177-5559)
- Michael Fine (ORCID: https://orcid.org/0000-0002-8436-3073)
- Aurélie Hatton (ORCID: https://orcid.org/0000-0002-8985-9625)
- Dawid Jaślan (ORCID: https://orcid.org/0000-0002-0685-7633)
- Nadia Elghobashi‐Meinhardt (ORCID: https://orcid.org/0000-0002-1023-6856)
- Nidish Ponath Sadanandan (ORCID: https://orcid.org/0000-0003-1534-831X)
- Philip Schmiege (ORCID: https://orcid.org/0000-0001-5703-7806)
- Xiaochun Li (ORCID: https://orcid.org/0000-0002-0177-0803)
Institutions
- University College Dublin (IE)
- Mansfield University (US)
- Bowdoin College (US)
- Southwestern Medical Center (US)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- Ludwig-Maximilians-Universität München (DE)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1038/s41467-025-60710-8
- Citations
- 1
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.12
Funders
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- University of Texas Southwestern Medical Center
- G. Harold and Leila Y. Mathers Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences