Cryo-EM structures of human pannexin 1 channel

Jin, Qiang; Zhang, Bo; Zheng, Xiang; Li, Ningning; Xu, Li; Xie, Yuan; Song, Fangjun; Bhat, Eijaz Ahmed; Chen, Yuan; Gao, Ning; Guo, Jiangtao; Zhang, Xiaokang; Ye, Sheng

doi:10.1038/s41422-020-0310-0

Cited by 50 publications

(57 citation statements)

References 14 publications

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“…5k and 6). In general, the oligomeric state, secondary and tertiary structure recapitulate that of the recent high-resolution cryoEM structures of Panx1 (Deng et al, 2020;Jin et al, 2020;Michalski et al, 2020;Mou et al, 2020;Qu et al, 2020;Ruan et al, 2020) (e.g., compare Figs. 7a and 7d).…”

Section: Negative-stain and Cryoem Analysis Demonstrated That Fpanx1δsupporting

confidence: 74%

“…Over the last ~15 years, Panx1 has been considered as a hexameric channel by analogy to Cx hemichannels (Baranova et al, 2004;Boassa et al, 2007;Bruzzone et al, 2003;Locovei et al, 2006a;Penuela et al, 2007), and based on previous empirical results from EM, chemical crosslinking, and single-molecule photobleaching (Ambrosi et al, 2010;Boassa et al, 2007;Chiu et al, 2017). In contrast, six publications in 2020 presented 16 independent, high-resolution cryoEM 3D reconstructions of various Panx1 constructs (Deng et al, 2020;Jin et al, 2020;Michalski et al, 2020;Mou et al, 2020;Qu et al, 2020;Ruan et al, 2020), which demonstrated that Panx1 assembles as a heptamer. In such studies the highest resolution is achieved by excluding the vast majority of the recorded particle images.…”

Section: Discussionmentioning

confidence: 99%

“…2). Interestingly, all of the high-resolution Panx1 structures display a narrow extracellular pore that would exclude ATP (Deng et al, 2020;Jin et al, 2020;Michalski et al, 2020;Qu et al, 2020;Ruan et al, 2020), even though constructs truncated at the C-tail caspase site (e.g., PDB 6WBG (Ruan et al, 2020) and PDB 6LTN (Mou et al, 2020)) should permit an open ATP-permeable conformation. Presumably, protein "breathing" would enable a wider extracellular pore that would accommodate hydrated ions, metabolites and signaling molecules like ATP.…”

Section: Comparison With Other Oligomeric 4-helix Bundle Large Porementioning

confidence: 99%

“…Similar to the impressive productivity in the structural biology of LRRC8A (SWELL1) channels, six publications appeared in 2020 describing 16 independent high-resolution, 3D cryoEM reconstructions of various constructs of frog and human Panx1 channels: PDB codes 6UZY, 6V6D (Deng et al, 2020), PDB codes 6M66, 6M67, 6M68 (Jin et al, 2020), PDB code 6VD7 (Michalski et al, 2020), PDB codes 6LTN, 6LTO (Mou et al, 2020), PDB code 6MO2 (Qu et al, 2020), PDB codes 6WBF, 6WBG, 6WBI, 6WBK, 6WBL, 6WBM, 6WBN (Ruan et al, 2020). All structures demonstrate that Panx1 assembles as a heptamer.…”

Section: Introductionmentioning

confidence: 96%

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A Constitutively Closed Pannexin1 Channel in Lipid Bilayer Nanodiscs Assembles as a Large-Pore Heptamer

Jin

Leonhardt

Chiu

et al. 2021

Preprint

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SUMMARYPannexin 1 (Panx1) channels are widely expressed and play important roles in apoptotic cell clearance, inflammation, blood pressure regulation, neurological disorders, opiate withdrawal, and cancer progression and metastasis. We performed (1) physicochemical analysis on a constitutively closed Panx1 channel (designated fPanx1ΔC) to examine the entire population of particles to detect multiple oligomeric states and (2) cryoEM in the membrane mimetics amphipol A8-35 and lipid bilayer nanodiscs. Our results reveal that the dominant if not exclusive oligomeric state of fPanx1ΔC is a heptamer, in solution and by cryoEM. The Panx1 heptamer provides further structural diversity within the family of large-pore channels, including hexameric LRRC8 (SWELL1) channels and connexin hemichannels, octameric CALHM1 channels and innexin hemichannels, and undecameric CALHM2 channels. Conserved structural themes are a large cytoplasmic vestibule with a diameter that corresponds roughly with the oligomeric state and a 4-helix bundle protomer, albeit with noncanonical helical packing for CALHM1 and CALHM2.In BriefThe 4-helix bundle protomer of a constitutively closed pannexin1 channel assembles as a heptamer in solution and by cryoEM.

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Section: Negative-stain and Cryoem Analysis Demonstrated That Fpanx1δsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Comparison With Other Oligomeric 4-helix Bundle Large Porementioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 2 more Smart Citations

A Constitutively Closed Pannexin1 Channel in Lipid Bilayer Nanodiscs Assembles as a Large-Pore Heptamer

Jin

Leonhardt

Chiu

et al. 2021

Preprint

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“…, 2004 ), respectively. The cryo-EM 3D structure of PANX1 (PDB: 6m66) was used as a model for all the visualizations ( Jin et al. , 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Pannexin 1 mutation found in melanoma tumor reduces phosphorylation, glycosylation, and trafficking of the channel-forming protein

Nouri‐Nejad

O'Donnell

Patil

et al. 2021

MBoC

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Pannexin 1 (PANX1) is a glycoprotein that forms large pore channels capable of passing ions and metabolites such as ATP for cellular communication. PANX1 has been implicated in many diseases including breast cancer and melanoma, where inhibition or deletion of PANX1 reduced the tumorigenic and metastatic properties of the cancer cells. We interrogated the effect of single amino acid changes in various PANX1 domains, using naturally occurring variants reported in cancer patient tumors. We found that a previously reported variant (Q5H), is present in cancer cells, but was not different from the wildtype (Q5) in glycosylation, trafficking, or channel function, and did not affect cellular properties. We discovered that the Q5H variant is in fact the highly conserved ancestral allele of PANX1, with 89% of humans carrying at least one Q5H allele. Another mutated form Y150F, found in a melanoma patient tumour, prevented phosphorylation at Y150 as well as complex N-glycosylation, while increasing intracellular localization. SRC is the predicted kinase to phosphorylate the Y150 residue, and its phosphorylation is not likely to be constitutive, but rather dynamically regulated. The Y150 phosphorylation site is the first one reported to play a role in regulating post-translational modifications and trafficking of PANX1, with potential consequences on its large-pore channel structure and function in melanoma cells.

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A novel heterozygous variant in PANX1 is associated with oocyte death and female infertility

Zou

et al. 2022

J Assist Reprod Genet

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Cryo-EM structures of human pannexin 1 channel

Cited by 50 publications

References 14 publications

A Constitutively Closed Pannexin1 Channel in Lipid Bilayer Nanodiscs Assembles as a Large-Pore Heptamer

A Constitutively Closed Pannexin1 Channel in Lipid Bilayer Nanodiscs Assembles as a Large-Pore Heptamer

Pannexin 1 mutation found in melanoma tumor reduces phosphorylation, glycosylation, and trafficking of the channel-forming protein

A novel heterozygous variant in PANX1 is associated with oocyte death and female infertility

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