期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 10, 页码 4238-4243出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1817271116
关键词
counter-ion mechanism; Ca2+ modulation; lipid modulation; X-ray crystallography; electrophysiology
资金
- National Key R&D Program of China [2016YFA0500503, 2015CB910102]
- Chinese Academy of Sciences Strategic Priority Research Program [XDB08020301]
- National Natural Science Foundation of China [31872721, 31470728, 31322005, 31728010, 11672226]
- National Thousand Young Talents program from the Office of Global Experts Recruitment in China
- Young Talent Support Plan of Xi'an Jiao-tong University
- State Key Laboratory of Molecular Developmental Biology, China [2018-MDB-KF-02]
- NIH [R01GM106037, GM 107462, P41 GM116799]
Trimeric intracellular cation (TRIC) channels are thought to provide counter-ion currents that facilitate the active release of Ca2+ from intracellular stores. TRIC activity is controlled by voltage and Ca2+ modulation, but underlying mechanisms have remained unknown. Here we describe high-resolution crystal structures of vertebrate TRIC-A and TRIC-B channels, both in Ca2+-bound and Ca2+-free states, and we analyze conductance properties in structure-inspired mutagenesis experiments. The TRIC channels are symmetric trimers, wherein we find a pore in each protomer that is gated by a highly conserved lysine residue. In the resting state, Ca2+ binding at the luminal surface of TRIC-A, on its threefold axis, stabilizes lysine blockage of the pores. During active Ca2+ release, luminal Ca2+ depletion removes inhibition to permit the lysine-bearing and voltage-sensing helix to move in response to consequent membrane hyperpolarization. Diacylglycerol is found at interprotomer interfaces, suggesting a role in metabolic control.
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