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- W3131983232 abstract "By mediating the purinergic signaling pathway, ATP release channels play a fundamental role in many neurological functions, including the modulation of excitatory synaptic strength, long-term synaptic potentiation, and neuronal excitability. The calcium homeostasis modulators are key ATP release channels consisting of three members, CALHM1, 2 and 3. CALHM channels plays essential roles in taste and neuron transmission, and their dysregulation has been associated with various neurological disorders including Alzheimer disease and ischemic brain damage. In the absence of Ca2+, the CALHMs are activated in a voltage-dependent manner, and the current can be inhibited by small molecules such as ruthenium red (RUR). The topology of CALHMs consists of four transmembrane domains (S1-S4) and a long cytosolic domain. Despite the importance of CALHM channels, their structures and functional properties are largely unexplored.We determined cryo-EM structures of full-length human CALHM2 in the Ca2+-free open state as both hemichannel and gap junction, and RUR-bound inhibited state at resolutions up to 2.7 Å. CALHM2 forms an unpreceded undecamer. We identified a RUR binding site located underneath the S1, where a mutation of a key residue (E37R) abolished RUR inhibition by patch-clamp electrophysiology. The primary determinants for the channel gate of CALHM2 are S1 and N-terminal helix (NTH), where remarkable conformational changes are observed when comparing the two functional states. The Ca2+-free hemichannel favors S1 in a vertical conformation, resulting in a large open pore. In the RUR-bound state, the RUR supports S1 in a lifted conformation, thus occluding the ion conducting pore. We propose a two-stage mechanism, whereby S1 adjusts the pore size coarsely and the NTH makes fine adjustments, eventually physically occluding the pore. Our work elucidates the molecular principles, overall architectures, stoichiometry of CALHM2 channel and its gating mechanism." @default.
- W3131983232 created "2021-03-01" @default.
- W3131983232 creator A5068445876 @default.
- W3131983232 date "2021-02-01" @default.
- W3131983232 modified "2023-10-18" @default.
- W3131983232 title "Structure Basis and Gating Mechanism of Calcium Homeostasis Modulator 2 Channel" @default.
- W3131983232 doi "https://doi.org/10.1016/j.bpj.2020.11.1424" @default.
- W3131983232 hasPublicationYear "2021" @default.
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