+Search query
-Structure paper
| Title | Reversible lipid-mediated pH-gating of connexin-46/50 by cryo-EM. |
|---|---|
| Journal, issue, pages | Nat Commun, Year 2026 |
| Publish date | Jan 12, 2026 |
Authors | Joshua M Jarodsky / Janette B Myers / Steve L Reichow / ![]() |
| PubMed Abstract | Gap junctions, formed by connexin proteins, establish direct electrical and metabolic coupling between cells, enabling coordinated tissue responses. These channels universally respond to ...Gap junctions, formed by connexin proteins, establish direct electrical and metabolic coupling between cells, enabling coordinated tissue responses. These channels universally respond to intracellular pH changes, closing under acidic conditions to limit the spread of cytotoxic signals during cellular stress, such as ischemia. Using cryo-electron microscopy (cryo-EM), we uncover insights into the structural mechanism of pH-gating in native lens connexin-46/50 (Cx46/50) gap junctions. Mild acidification drives lipid infiltration into the channel pore, displacing the N-terminal (NT) domain and stabilizing pore closure. Lipid involvement is shown to be both essential and fully reversible. Structural transitions involve an ensemble of gated states formed through non-cooperative NT domain movement as well as minor populations of a distinct destabilized open-state. These findings provide molecular insights into pH-gating dynamics, illustrating how structural changes may regulate gap junction function under cellular stress and linking Cx46/50 dysregulation to age-related cataract formation. |
External links | Nat Commun / PubMed:41526355 |
| Methods | EM (single particle) |
| Resolution | 2.0 - 2.7 Å |
| Structure data | EMDB-73876: Stable open sheep connexin-46/50 in amphipol at low pH EMDB-73885: Stable open state sheep connexin-46/50 in DMPC nanodiscs at neutral pH EMDB-73896, PDB-9z8f: EMDB-73900: Gated state sheep connexin-46/50 in DMPC nanodiscs at neutral pH EMDB-73942: Stable open state sheep connexin-46/50 in DMPC nanodiscs at low pH EMDB-73957: Destabilized open state sheep connexin-46/50 in DMPC nanodiscs at low pH EMDB-73962: Gated state sheep connexin-46/50 in DMPC nanodiscs at low pH EMDB-73965: Asymmetrically gated state sheep connexin-46/50 in DMPC nanodiscs at low pH ![]() PDB-9z9y: |
| Chemicals | ![]() ChemComp-MC3: ![]() ChemComp-HOH: |
| Source |
|
Keywords | MEMBRANE PROTEIN / connexin / gap junction / cryo-EM / pH regulation / lipid gating / large-pore channel |
Movie
Controller
Structure viewers
About Yorodumi Papers



Authors
External links


























Keywords