The group of Tim Springer at Children's Hospital Boston and Harvard University determined the crystal structure of the macromolecular complex of one integrin αVβ6 bound to one transforming growth factor-β1 precursor (pro-TGF-β1) dimer. The integrin adhesion receptors 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 to an extended form. This work shows how integrin αVβ6 binds pro-TGF-β1 in an orientation biologically relevant for force-dependent release of TGF-β from it compact latent state. 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 the extracellular matrix. Regions in and outside the highly interdigitated interface stabilize a specific integrin/pro-TGF-β orientation that defines the pathway through these macromolecules for the actin-cytoskeleton-generated tensile force 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. TGF-β1 is synthesized and secreted in the inactive form of pro-TGF-β1 and is anchored by milieu protein (LTBP or GARP) in the ECM or on the cell surface. Integrin αVβ6 binds to the bowtie tail region of pro-TGF-β1 prodomain, and tensile forces generated by the cytoskeleton are transmitted through the integrin β-leg to pro-TGF-β1, disrupting the conformation of the prodomain and releasing the mature (extended) TGF-β1 growth factor for subsequent receptor binding and cell signaling.
Crystal structure of the macromolecular complex of one integrin αVβ6 (green and orange) bound to one transforming growth factor-β1 precursor (pro-TGF-β1) dimer (magenta and pink).
Dong X, Zhao B, Iacob RE, Zhu J, Koksal AC, Lu C, Engen JR, Springer TA. "Force interacts with macromolecular structure in activation of TGF-β," Nature 542 (7639), 55-59 (2017). DOI: 10.1038/natur21035