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Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å

Author

Listed:
  • Jonathan A. Flores

    (Oregon Health and Science University)

  • Bassam G. Haddad

    (Portland State University)

  • Kimberly A. Dolan

    (Portland State University
    University of California)

  • Janette B. Myers

    (Portland State University)

  • Craig C. Yoshioka

    (Oregon Health and Science University)

  • Jeremy Copperman

    (Oregon Health and Science University)

  • Daniel M. Zuckerman

    (Oregon Health and Science University)

  • Steve L. Reichow

    (Oregon Health and Science University
    Portland State University)

Abstract

Gap junctions establish direct pathways for cells to transfer metabolic and electrical messages. The local lipid environment is known to affect the structure, stability and intercellular channel activity of gap junctions; however, the molecular basis for these effects remains unknown. Here, we incorporate native connexin-46/50 (Cx46/50) intercellular channels into a dual lipid nanodisc system, mimicking a native cell-to-cell junction. Structural characterization by CryoEM reveals a lipid-induced stabilization to the channel, resulting in a 3D reconstruction at 1.9 Å resolution. Together with all-atom molecular dynamics simulations, it is shown that Cx46/50 in turn imparts long-range stabilization to the dynamic local lipid environment that is specific to the extracellular lipid leaflet. In addition, ~400 water molecules are resolved in the CryoEM map, localized throughout the intercellular permeation pathway and contributing to the channel architecture. These results illustrate how the aqueous-lipid environment is integrated with the architectural stability, structure and function of gap junction communication channels.

Suggested Citation

  • Jonathan A. Flores & Bassam G. Haddad & Kimberly A. Dolan & Janette B. Myers & Craig C. Yoshioka & Jeremy Copperman & Daniel M. Zuckerman & Steve L. Reichow, 2020. "Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18120-5
    DOI: 10.1038/s41467-020-18120-5
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    Cited by:

    1. Hyuk-Joon Lee & Hyung Jin Cha & Hyeongseop Jeong & Seu-Na Lee & Chang-Won Lee & Minsoo Kim & Jejoong Yoo & Jae-Sung Woo, 2023. "Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Hwa-Jin Cho & Dong Kyu Chung & Hyung Ho Lee, 2024. "Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Seu-Na Lee & Hwa-Jin Cho & Hyeongseop Jeong & Bumhan Ryu & Hyuk-Joon Lee & Minsoo Kim & Jejoong Yoo & Jae-Sung Woo & Hyung Ho Lee, 2023. "Cryo-EM structures of human Cx36/GJD2 neuronal gap junction channel," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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