Cell biology

Biology

Receptor

Biochemistry

Transient receptor potential channel

Ligand (biochemistry)

Allosteric regulation

Chemistry

Biophysics

Proceedings of the National Academy of Sciences

Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] as well as some synthetic small-molecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P2 and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P2 and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo-EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P2-bound closed, and PI(3,5)P2/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.

Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P <sub>2</sub> and rapamycin

Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P 2 and rapamycin

Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P ₂ and rapamycin