Amira Gabrielle M. Cantos | Kim Ivan A. Abesamis | Camille Anne S. Bagoyo | Neil Andrew D. Bascos
Integrins are a family of cell-surface receptors that mediate cell-matrix and cell-cell adhesion. Each member is a heterodimer comprised of non-covalently associated alpha and beta subunits, whose identities in each integrin direct ligand specificities and function. In vertebrates, 18α and 8β subunits associate to form 24 unique heterodimers. The α6 integrin subunit pairs with either β1 or β4, but both heterodimers are receptors for laminin. Neither α6β1 nor α6β4 have deposited crystal structures. In this study, the structures of the ligand-binding domains (LBDs) of integrins α6β1 and α6β4 were predicted, and these models were analyzed computationally. In silico Alanine substitutions across the protein sequence predicted hotspots of interaction primarily at Tyr, Asp, and Arg residues for both β1 and β4. To compare the two α6 integrins, the models of the LBDs of α6β1 and α6β4 were assessed based on inter-subunit binding affinity. This was predicted to be higher for α6β4, which may be attributed to its role in promoting cellular adhesion and maintaining stability in the intermediate filament system. To determine the behavior of α6β1 and α6β4 in different environments, the models were equilibrated in NaCl and CaCl2. In agreement with binding affinity predictions, steered molecular dynamics (SMD) yielded higher rupture forces for α6β4 than for α6β1 in both environments. The rupture force of α6β1 was higher in NaCl (4658.61 kJ mol-1 nm-1) than in CaCl2 (4349.82 kJ mol-1 nm-1), which may be explained by the greater number of H-bonds and larger inter-subunit binding interface exhibited by α6β1 in NaCl. In contrast, α6β4 separates later and with a greater rupture force in CaCl2 (5931.96 kJ mol-1 nm-1) than in NaCl (4662.51 kJ mol-1 nm-1). These results suggest that α6β4 dimerizes more readily than α6β1, and that their binding affinities change in different ion environments.
ISSN 2719-1990 (Print)
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