Gap junction (GJ) channel mediates direct intercellular communication and is composed of two docked hemichannels (connexin oligomers). It is well documented that the docking and formation of GJs are possible only between compatible hemichannels (or connexins). The mechanisms of heterotypic docking compatibility are not fully clear. We aligned the protein sequences of docking compatible and incompatible connexins with that of Cx26. We found that two docking hydrogen bond-forming residues on the second extracellular domain (E2) of Cx26 and their equivalent residues are well conserved within docking compatible connexins, but different between docking incompatible connexins. Replacing one or both of these residues of Cx26 into the corresponding residues in the docking incompatible connexins (K168V, N176H or K168V-N176H) increased the formation of morphological and functional heterotypic GJs with Cx43 (or Cx40), indicating these two residues are important for docking incompatibility between Cx26 and these connexins. Our homology structure models predict that both hydrogen bonds and hydrophobic interactions at the E2 docking interface are important docking mechanisms in heterotypic Cx26 K168V-N176H/Cx43 GJs and likely other docking compatible connexins. Revealing the key residues and mechanisms of heterotypic docking compatibility will assist us in understanding why these putative docking residues are hotspots of disease-linked mutants.
- gap junction channel
- docking mechanism
- ©2016 The Author(s)
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