Cryo-EM structure of the heptameric calcium homeostasis modulator 1 channel

Ren, Yue; Li, Yang; Wang, Yaojie; Wen, Tianlei; Lu, Xuhang; Chang, Shenghai; Zhang, Xing; Shen, Yuequan; Yang, Xue

doi:10.1016/j.jbc.2022.101838

Cited by 12 publications

(11 citation statements)

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“…This NTH orientation maximally sets the pore-diameter to be >14 Å between fully extended side chains (e.g., Gln13 - the side chain density is not resolved), which is sufficiently large to conduct ATP and ions 21 . We speculate that closure of the channel is mediated by the highly dynamic nature of the NTHs, which disrupts the NTH pore architecture in a stochastic manner, as the recent MD simulations study indicated 22 . The architecture and motion of the TMD1-NTH region are analogous to that of the arm, elbow joint, and forearm, with the NTH (“forearm”) permitted a range of motion.…”

Section: Discussionmentioning

confidence: 86%

Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red

et al. 2023

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Calcium homeostasis modulator 1 (CALHM1) is a voltage-dependent channel involved in neuromodulation and gustatory signaling. Despite recent progress in the structural biology of CALHM1, insights into functional regulation, pore architecture, and channel blockade remain limited. Here we present the cryo-EM structure of human CALHM1, revealing an octameric assembly pattern similar to the non-mammalian CALHM1s and the lipid-binding pocket conserved across species. We demonstrate by MD simulations that this pocket preferentially binds a phospholipid over cholesterol to stabilize its structure and regulate the channel activities. Finally, we show that residues in the amino-terminal helix form the channel pore that ruthenium red binds and blocks.

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Section: Discussionmentioning

confidence: 86%

Structure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red

et al. 2023

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“…Unlike other channels with fixed numbers of protomers in oligomeric assembly, CALHM members showed quite variable oligomeric compositions (Fig. S5A): 7-mer (CALHM1) (Ren et al , 2022), 8-mer (CALHM1) (Demuraet al , 2020;Ren et al , 2020;Syrjanen et al , 2020;Ren et al , 2022), 9-mer (C. elegans CLHM-1) (Demuraet al , 2020), 10-mer (CALHM5/6) (Drozdzyk et al , 2020), 11-mer (CALHM2/5/6) (Choi et al , 2019;Demura et al , 2020;Syrjanen et al , 2020), 12-mer (CALHM5) (Liu et al , 2020) and 13-mer (CALHM5) (Liu et al , 2020). In addition to forming (hemi)channels, CALHMs also assemble into junctions in a tail-to-tail or head-to-head configuration, also with different oligomeric states (Fig.…”

Section: Calcium Homeostasis Modulators (Calhms) Non-selective Channe...mentioning

confidence: 93%

To be or not to be an ion channel: cryo-EM structures have a say

Chen

Zhang

et al. 2023

Preprint

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Identification of previously unknown ion channels is always a challenging work though the transmembrane protein-coding genes in human genome has been comprehensively annotated for years. Despite being the gold standard of functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance and background currents of the membrane system. These unwanted signals, if not treated properly, lead to mischaracterization of proteins with seemingly unusual ion-conducting properties. In recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) have greatly advanced our understanding on the structures and gating mechanisms of various ion channels, and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years, and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships, and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function.

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“…Interestingly, VRAC is now known to be related to the pannexins: LRRC8a has a pannexin-like channel core with a very large cytoplasmic elaboration consisting of the leucine-rich repeats (Abascal and Zardoya, 2012;Jentsch et al, 2016;Kasuya et al, 2018;Kefauver et al, 2018;Qiu et al, 2014;Voss et al, 2014). The CalHMs, while having a variable stoichiometry of at least 7 subunits and as many as 11, also have an N-terminal helix that projects into the pore (Choi et al, 2019;Demura et al, 2020;Drożdżyk et al, 2020;Ren et al, 2022;Syrjanen et al, 2020;Yang et al, 2020). The P2X7 receptor and its ability to release ATP requires further discussion.…”

Section: Channels Capable Of Releasing Atpmentioning

confidence: 99%