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Author(s): Xianchi Dong [1]; Bo Zhao [1]; Roxana E. Iacob [2]; Jianghai Zhu [1]; Adem C. Koksal [1]; Chafen Lu [1]; John R. Engen [2]; Timothy A. Springer (corresponding author) [...], Integrins are adhesion receptors that transmit force across the plasma membrane between extracellular ligands and the actin cytoskeleton. In activation of the transforming growth factor-1 precursor (pro-TGF-1), integrins bind to the prodomain, apply force, and release the TGF- growth factor. However, we know little about how integrins bind macromolecular ligands in the extracellular matrix or transmit force to them. Here we show how integrin [sub.V][sub.6] binds pro-TGF-1 in an orientation biologically relevant for force-dependent release of TGF- from latency. The conformation of the prodomain integrin-binding motif differs in the presence and absence of integrin binding; differences extend well outside the interface and illustrate how integrins can remodel extracellular matrix. Remodelled residues outside the interface stabilize the integrin-bound conformation, adopt a conformation similar to earlier-evolving family members, and show how macromolecular components outside the binding motif contribute to integrin recognition. Regions in and outside the highly interdigitated interface stabilize a specific integrin/pro-TGF- orientation that defines the pathway through these macromolecules which actin-cytoskeleton-generated tensile force takes when applied through the integrin -subunit. Simulations of force-dependent activation of TGF- demonstrate evolutionary specializations for force application through the TGF- prodomain and through the - and not -subunit of the integrin.