title: Force interacts with macromolecular structure in activation of TGF-β.
abstract: 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-β1 precursor (pro-TGF-β1), integrins bind to the prodomain, apply force, and release the TGF-β 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 αVβ6binds pro-TGF-β1 in an orientation biologically relevant for force-dependent release of TGF-β 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-β orientation that defines the pathway through these macromolecules which actin-cytoskeleton-generated tensile force takes when applied through the integrin β-subunit. Simulations of force-dependent activation of TGF-β demonstrate evolutionary specializations for force application through the TGF-β prodomain and through the β- and not α-subunit of the integrin.
authors.affiliation: Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xianchi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Iacob
authors.affiliation: Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jianghai
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Adem C
authors.initials: AC
authors.lastname: Koksal
authors.affiliation: Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chafen
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
authors.affiliation: Children's Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D016023:Integrins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D053773:Transforming Growth Factor beta1 / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6