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bioRxiv · 10.1101/2023.07.19.549697

Simulation of gap junction formation reveals critical role of cysteines in connexon coupling

Heja, L.·Simon, A.·Kardos, J.
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Abstract

Despite the fundamental functions of connexin gap junctions (CxGJs), understanding of molecular mechanisms, governing intercellular CxGJ formation by coupling of connexon hemichannels (CxHCs, connexons) is still in infancy. In silico simulation of intercellular connexon coupling of two Cx43HC models, embedded in membrane bilayers (Cx43HC-HC) successfully modelled the emergence of trans-gap junctional (trans-GJ) stabilization centers (SCs). Investigating the molecular determinants shaping the HC-HC interface, we revealed that the exceptionally high number of cysteine residues located at the interface play a pivotal role in the stabilization of HC and GJ structures. Opening of the disulphide bonds between these cysteines resulted in disappearance of trans-GJ SCs in the Cx43GJ model. In contrast, the Cx43HC form was found to be consistent with open disulphide bonds. Finally, we have shown that the presence of an adjoining HC contributes to disulphide formation and consequently to the emergence of trans-GJ H-bonds. Our results suggest that several connexon channels in vertebrates may undertake intercellular connexon coupling similarly and may bring forward to the targeting of CxGJ-specific coupling.

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Heja, L., Simon, A., Kardos, J.. 2023-07-21. Simulation of gap junction formation reveals critical role of cysteines in connexon coupling. https://doi.org/10.1101/2023.07.19.549697

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