TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family

Philip Schmiege, Dawid Jaślan, Michael Fine, Nidish Ponath Sadanandan, Alexandra Hatton, Nadia Elghobashi-Meinhardt, Christian Grimm () and Xiaochun Li ()
Additional contact information
Philip Schmiege: University of Texas Southwestern Medical Center
Dawid Jaślan: Ludwig Maximilian University of Munich
Michael Fine: Bowdoin College
Nidish Ponath Sadanandan: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
Alexandra Hatton: University of Texas Southwestern Medical Center
Nadia Elghobashi-Meinhardt: University College Dublin
Christian Grimm: Ludwig Maximilian University of Munich
Xiaochun Li: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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)P2 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-60710-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60710-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-60710-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().