Fuzzy binding model of molecular interactions between tropoelastin and integrin alphaVbeta3

Abstract

Tropoelastin is the highly flexible monomer subunit of elastin, required for the resilience of the extracellular matrix in elastic tissues. To elicit biological signaling, multiple sites on tropoelastin bind to cell surface integrins in a poorly understood multifactorial process. We constructed a full atomistic molecular model of the interactions between tropoelastin and integrin α_vβ₃ using ensemble-based computational methodologies. Conformational changes of integrin α_vβ₃ associated with outside-in signaling were more frequently facilitated in an ensemble in which tropoelastin bound the integrin's α1 helix rather than the upstream canonical binding site. Our findings support a model of fuzzy binding, whereby many tropoelastin conformations and defined sites cooperatively interact with multiple α_vβ₃ regions. This model explains prior experimental binding to distinct tropoelastin regions, domains 17 and 36, and points to the cooperative participation of domain 20. Our study highlights the utility of ensemble-based approaches in helping to understand the interactive mechanisms of functionally significant flexible proteins.