Title : Cryo-EM structures of the human endolysosomal
TRPML3 channel in three distinct states
Abstract :
- TRPML3 channels are mainly localized to endolysosomes and play a critical role in the endocytic pathway
- Their dysfunction causes deafness and pigmentation defects in mice
- TRPML3 activity is inhibited by low endolysosomal pH. Here we present cryo-electron microscopy (cryo-EM) structures of human TRPML3 in the closed, agonist-activated, and low-pH-inhibited states, with resolutions of 4.06, 3.62, and 4.65 Å, respectively
- The agonist ML- SA1 lodges between S5 and S6 and opens an S6 gate
- A polycystin-mucolipin domain (PMD) forms a luminal cap
- S1 extends into this cap, forming a 'gating rod' that connects directly to a luminal pore loop, which undergoes dramatic conformational changes in response to low pH. S2 extends intracellularly and interacts with several intracellular regions to form a 'gating knob'
- These unique structural features, combined with the results of electrophysiological studies, indicate a new mechanism by which luminal pH and other physiological modulators such as PIP2 regulate TRPML3 by changing S1 and S2 conformations
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