2. Academic Validation
  3. Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states

Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states

  • Nat Struct Mol Biol. 2017 Dec;24(12):1146-1154. doi: 10.1038/nsmb.3502.
Xiaoyuan Zhou 1,  Minghui Li 2,  Deyuan Su 2 3,  Qi Jia 4,  Huan Li 3 5,  Xueming Li 1,  Jian Yang 2 3
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 2 Department of Biological Sciences, Columbia University, New York, New York, USA.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, and Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 4 Department of Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
  • 5 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
PMID: 29106414 DOI: 10.1038/nsmb.3502
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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