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论文题目: Cryo-EM Structures of the Human Endolysosomal TRPML3 Channel in Three Distinct States
作者: Zhou X, Li M, Su D, Jia Q, Li H, Li X, Yang J
联系作者: Yang J
发表年度: 2017
DOI: doi: 10.1038/nsmb.3502
摘要:

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

刊物名称: Nature Structural Molecular & Biology
论文出处: https://www.nature.com/articles/nsmb.3502
影响因子: 12.596(2016年)