Arrhythmogenic cardiomyopathy-related cadherin variants affect desmosomal binding kinetics.

Autor: Göz M; Department of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld University, Universitätsstraße 25, Bielefeld, Germany., Pohl G; Erich & Hanna Klessmann Institute for Cardiovascular Research and Development, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstraße 11, Bad Oeynhausen, Germany., Steinecker SM; Department of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld University, Universitätsstraße 25, Bielefeld, Germany., Walhorn V; Department of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld University, Universitätsstraße 25, Bielefeld, Germany. Electronic address: volker.walhorn@physik.uni-bielefeld.de., Milting H; Erich & Hanna Klessmann Institute for Cardiovascular Research and Development, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstraße 11, Bad Oeynhausen, Germany., Anselmetti D; Department of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld University, Universitätsstraße 25, Bielefeld, Germany.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Oct; Vol. 195, pp. 36-44. Date of Electronic Publication: 2024 Jul 28.
DOI: 10.1016/j.yjmcc.2024.07.009
Abstrakt: Cadherins are calcium dependent adhesion proteins that establish and maintain the intercellular mechanical contact by bridging the gap between adjacent cells. Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) are tissue specific cadherin isoforms of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2-gene and in the DSC2-gene are related to arrhythmogenic right ventricular cardiomyopathy (ARVC) a rare but severe heart muscle disease. Here, several possible homophilic and heterophilic binding interactions of wild-type Dsg2, wild-type Dsc2, as well as one Dsg2- and two Dsc2-variants, each associated with ARVC, are investigated. Using single molecule force spectroscopy (SMFS) with atomic force microscopy (AFM) and applying Jarzynski's equality the kinetics and thermodynamics of Dsg2/Dsc2 interaction can be determined. The free energy landscape of Dsg2/Dsc2 dimerization exposes a high activation energy barrier, which is in line with the proposed strand-swapping binding motif. Although the binding motif is not affected by any of the mutations, the binding kinetics of the interactions differ significantly from the wild-type. While wild-type cadherins exhibit an average complex lifetime of approx. 0.3 s interactions involving a variant consistently show - lifetimes that are substantially larger. The lifetimes of the wild-type interactions give rise to the picture of a dynamic adhesion interface consisting of continuously dissociating and (re)associating molecular bonds, while the delayed binding kinetics of interactions involving an ARVC-associated variant might be part of the pathogenesis. Our data provide a comprehensive and consistent thermodynamic and kinetic description of cardiac cadherin binding, allowing detailed insight into the molecular mechanisms of cell adhesion.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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