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| Title | Lipid dependence of connexin-32 gap junction channel conformations. |
|---|---|
| Journal, issue, pages | Nat Commun, Year 2025 |
| Publish date | Dec 5, 2025 |
Authors | Pia Lavriha / Carina Fluri / Jorge Enrique Hernández González / Volodymyr M Korkhov / ![]() |
| PubMed Abstract | Connexin-32 (Cx32) gap junction channels (GJCs) mediate intercellular coupling in various tissues, including myelinating Schwann cells. Mutations in Cx32, such as W3S, are associated with X-linked ...Connexin-32 (Cx32) gap junction channels (GJCs) mediate intercellular coupling in various tissues, including myelinating Schwann cells. Mutations in Cx32, such as W3S, are associated with X-linked Charcot-Marie-Tooth (CMT1X) disease. Lipids regulate Cx32 GJC permeation, although the regulatory mechanism is unclear. Here, we determine the cryo-EM structures of Cx32 GJCs reconstituted in nanodiscs, revealing that phospholipids block the Cx32 GJC pore by binding to the site formed by N-terminal gating helices. The phospholipid-bound state is contingent on the presence of a sterol molecule in a hydrophobic pocket formed by the N-terminus: the N-terminal helix of Cx32 fails to sustain a phospholipid binding site in the absence of cholesterol hemisuccinate. The CMT1X-linked W3S mutant which has an impaired sterol binding site adopts a conformation of the N-terminus incompatible with phospholipid binding. Our results indicate that different lipid species control connexin channel gating directly by influencing the conformation of the N-terminal gating helix. |
External links | Nat Commun / PubMed:41350533 |
| Methods | EM (single particle) |
| Resolution | 2.35 - 3.29 Å |
| Structure data | EMDB-53240, PDB-9qn9: EMDB-53244, PDB-9qnd: EMDB-53245, PDB-9qnf: EMDB-53250, PDB-9qnt: |
| Chemicals | ![]() ChemComp-POV: ![]() ChemComp-CLR: |
| Source |
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Keywords | MEMBRANE PROTEIN / Ion channel / gap junction / membrane transport / Gap junction channel / connexin-32 / lipids |
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homo sapiens (human)
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