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TitleA Steric "Ball-and-Chain" Mechanism for pH-Mediated Regulation of Gap Junction Channels.
Journal, issue, pagesCell Rep, Vol. 31, Issue 3, Page 107482, Year 2020
Publish dateApr 21, 2020
AuthorsAli K Khan / Maciej Jagielnicki / William E McIntire / Michael D Purdy / Venkatasubramanian Dharmarajan / Patrick R Griffin / Mark Yeager /
PubMed AbstractGap junction channels (GJCs) mediate intercellular communication and are gated by numerous conditions such as pH. The electron cryomicroscopy (cryo-EM) structure of Cx26 GJC at physiological pH ...Gap junction channels (GJCs) mediate intercellular communication and are gated by numerous conditions such as pH. The electron cryomicroscopy (cryo-EM) structure of Cx26 GJC at physiological pH recapitulates previous GJC structures in lipid bilayers. At pH 6.4, we identify two conformational states, one resembling the open physiological-pH structure and a closed conformation that displays six threads of density, that join to form a pore-occluding density. Crosslinking and hydrogen-deuterium exchange mass spectrometry reveal closer association between the N-terminal (NT) domains and the cytoplasmic loops (CL) at acidic pH. Previous electrophysiologic studies suggest an association between NT residue N14 and H100 near M2, which may trigger the observed movement of M2 toward M1 in our cryo-EM maps, thereby accounting for additional NT-CL crosslinks at acidic pH. We propose that these pH-induced interactions and conformational changes result in extension, ordering, and association of the acetylated NT domains to form a hexameric "ball-and-chain" gating particle.
External linksCell Rep / PubMed:32320665 / PubMed Central
MethodsEM (single particle)
Resolution4.0 - 7.5 Å
Structure data

20914

6uvr

EMDB-20914, PDB-6uvr:
Human Connexin-26 (Neutral pH open conformation)
Method: EM (single particle) / Resolution: 4.0 Å

20915

6uvs

EMDB-20915, PDB-6uvs:
Human Connexin-26 (Low pH open conformation)
Method: EM (single particle) / Resolution: 4.2 Å

20916

6uvt

EMDB-20916, PDB-6uvt:
Human Connexin-26 (Low pH closed conformation)
Method: EM (single particle) / Resolution: 7.5 Å

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / gap junction channel

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