Schmiege Philip, Jaślan Dawid, Fine Michael, Sadanandan Nidish Ponath, Hatton Alexandra, Elghobashi-Meinhardt Nadia, Grimm Christian, Li Xiaochun
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Pharmacology and Toxicology, Medical Faculty, Ludwig Maximilian University of Munich, Munich, Germany.
Nat Commun. 2025 Jun 17;16(1):5325. doi: 10.1038/s41467-025-60710-8.
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 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.
瞬时受体电位黏蛋白2（TRPML2）的活性对于内溶酶体完整性和趋化因子分泌至关重要，并且可被多种配体调节。有趣的是，两种ML-SI3异构体对TRPML2的调节作用相反。这种独特的异构体偏好以及TRPML2激动机制背后的分子机制仍然未知。在此，我们展示了处于不同状态的人TRPML2的六个冷冻电镜结构，揭示了S6的π-凸起在激动剂结合后发生π-α转变，突出了π-凸起在离子通道调节中的显著作用。此外，我们确定磷脂酰肌醇-3,5-二磷酸（PI(3,5)P）变构影响TRPML2特异性激活剂ML2-SA1的构象，导致通道开放而不发生π-α转变。功能和结构研究表明，将TRPML1的S5突变为TRPML2的S5能使突变后的TRPML1被(+)ML-SI3和ML2-SA1激活。因此，我们的工作阐明了TRPML通道的激活机制，并为开发选择性TRPML调节剂铺平了道路。
