| Autor: |
Manuel Göz, Sylvia M. Steinecker, Greta M. Pohl, Volker Walhorn, Hendrik Milting, Dario Anselmetti |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Scientific Reports, Vol 14, Iss 1, Pp 1-8 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-024-52725-w |
| Popis: |
Abstract The cardiac muscle consists of individual cardiomyocytes that are mechanically linked by desmosomes. Desmosomal adhesion is mediated by densely packed and organized cadherins which, in presence of Ca2+, stretch out their extracellular domains (EC) and dimerize with opposing binding partners by exchanging an N-terminal tryptophan. The strand-swap binding motif of cardiac cadherins like desmocollin 2 (Dsc2) (and desmoglein2 alike) is highly specific but of low affinity with average bond lifetimes in the range of approximately 0.3 s. Notably, despite this comparatively weak interaction, desmosomes mediate a stable, tensile-resistant bond. In addition, force mediated dissociation of strand-swap dimers exhibit a reduced bond lifetime as external forces increase (slip bond). Using atomic force microscopy based single molecule force spectroscopy (AFM-SMFS), we demonstrate that Dsc2 has two further binding modes that, in addition to strand-swap dimers, most likely play a significant role in the integrity of the cardiac muscle. At short interaction times, the Dsc2 monomers associate only loosely, as can be seen from short-lived force-independent bonds. These ideal bonds are a precursor state and probably stabilize the formation of the self-inhibiting strand-swap dimer. The addition of tryptophan in the measurement buffer acts as a competitive inhibitor, preventing the N-terminal strand exchange. Here, Dsc2 dimerizes as X-dimer which clearly shows a tri-phasic slip-catch-slip type of dissociation. Within the force-mediated transition (catch) regime, Dsc2 dimers switch between a rather brittle low force and a strengthened high force adhesion state. As a result, we can assume that desmosomal adhesion is mediated not only by strand-swap dimers (slip) but also by their precursor states (ideal bond) and force-activated X-dimers (catch bond). |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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