Short talk:
A redox-dependent thiol-switch and a Ca2+ binding site within the hinge region hierarchically depend on each other in α7β1 integrin regulation

Johannes Eble1, Michele F. Caliandro1, Luca Matteo Todesca2, Matthias Mörgelin3, Albrecht Schwab2

1University of Münster, Institute of Physiological Chemistry and Pathobiochemistry, Münster,  Germany,
2University of Münster, Institute of Physiology II, Münster, Germany,
3em3, Anderslöv,  Sweden

Integrin-mediated cell contacts with the extracellular matrix (ECM) are essential for cellular  adhesion, force transmission, and migration. Several effectors, such as divalent cations and  redox-active compounds, regulate ligand binding activities of integrins and influence their  cellular functions. To study the role of the Ca2+ binding site within the hinge region of the integrin  α7 subunit, we genetically abrogated it in the α7hiΔCa mutant. This mutant folded correctly,  associated with the β1 subunit and was exposed on the cell surface, but showed reduced ligand  binding and weaker cell adhesion to its ligand, laminin-111. Thus, it resembles the α7hiΔSS  mutant, in which the redox-regulated pair of cysteines, closeby to the Ca2+ binding site within the  hinge, was abrogated. By comparing both mutants in adhesion strength and cell migration, we  show that both Ca2+ complexation and redox-regulation within the hinge interdepend on each  other. Moreover, protein-chemical analyses of soluble integrin ectodomains containing the same  α7 hinge mutations suggest that integrin activation via the subunit α hinge is primed by the  formation of the cysteine pair–based crosslinkage. Then, this allows Ca2+ complexation within  the hinge, which is another essential step for integrin activation and ligand binding. Thus, the α  hinge is an allosteric integrin regulation site, in which both effectors, Ca2+ and redox-active  compounds, synergistically and hierarchically induce far-ranging conformational changes, such  as the extension of the integrin ectodomain, resulting in integrin activation of ECM ligand  binding and altered integrin-mediated cell functions.



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