Force activation of TGF-β

Tim Springer group (Harvard University)


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



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