National Basic Research Program of China (973 Program)
2014CB910301
中国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM085234
米国
National Natural Science Foundation of China (NSFC)
31370821
中国
Top Talents Program of Yunnan Province
2011HA012
中国
High-level Overseas Talents of Yunnan Province
中国
China Youth 1000-Talent Program of the State Council of China
中国
Beijing Advanced Innovation Center for Structural Biology
中国
Tsinghua-Peking Joint Center for Life Sciences
中国
National Natural Science Foundation of China (NSFC)
31570730
中国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2017 タイトル: Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. 著者: Xiaoyuan Zhou / Minghui Li / Deyuan Su / Qi Jia / Huan Li / Xueming Li / Jian Yang / 要旨: 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 ...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 PIP regulate TRPML3 by changing S1 and S2 conformations.