Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 24, Issue 12, Pages 1146-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3502
Keywords
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Funding
- National Basic Research Program of China [2014CB910301]
- National Institutes of Health [R01GM085234]
- National Natural Science Foundation of China [31370821, 31570730]
- National Key Research and Development Program [2016YFA0501102, 2016YFA0501902]
- Top Talents Program of Yunnan Province [2011HA012]
- High-level Overseas Talents of Yunnan Province
- China Youth 1000-Talent Program of the State Council of China
- Beijing Advanced Innovation Center for Structural Biology
- Tsinghua-Peking Joint Center for Life Sciences
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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 angstrom, 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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