Cryo-EM structures of human Cx36/GJD2 neuronal gap junction channel

Seu Na Lee, Hwa Jin Cho, Hyeongseop Jeong, Bumhan Ryu, Hyuk Joon Lee, Minsoo Kim, Jejoong Yoo, Jae Sung Woo, Hyung Ho Lee

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Connexin 36 (Cx36) is responsible for signal transmission in electrical synapses by forming interneuronal gap junctions. Despite the critical role of Cx36 in normal brain function, the molecular architecture of the Cx36 gap junction channel (GJC) is unknown. Here, we determine cryo-electron microscopy structures of Cx36 GJC at 2.2–3.6 Å resolutions, revealing a dynamic equilibrium between its closed and open states. In the closed state, channel pores are obstructed by lipids, while N-terminal helices (NTHs) are excluded from the pore. In the open state with pore-lining NTHs, the pore is more acidic than those in Cx26 and Cx46/50 GJCs, explaining its strong cation selectivity. The conformational change during channel opening also includes the α-to-π-helix transition of the first transmembrane helix, which weakens the protomer-protomer interaction. Our structural analyses provide high resolution information on the conformational flexibility of Cx36 GJC and suggest a potential role of lipids in the channel gating.

Original languageEnglish
Article number1347
JournalNature communications
Volume14
Issue number1
DOIs
Publication statusPublished - 2023 Dec

Bibliographical note

Funding Information:
This work was supported by the Suh Kyungbae Foundation (SUHF-18010097 to J.-S.W.), the National Research Foundation (NRF) grants funded by the Ministry of Science and ICT (NRF-2018R1C1B6004447 to J.-S.W. and NRF-2020R1A2C1101424 to J.Y.), and by the National Supercomputing Center (KSC-2020-CRE-0080 to J.Y.). This work was also supported by Samsung Science & Technology Foundation and Research (SSTF-BA2101-13) and the NRF grants (2015M3D3A1A01064919, 2022R1A2B5B02002529, 2022R1A5A6000760) to H.H.L.

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology

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