Force interacts with macromolecular structure in activation of TGF-β

Xianchi Dong, Bo Zhao, Roxana E. Iacob, Jianghai Zhu, Adem C. Koksal, Chafen Lu, John R. Engen and Timothy A. Springer ()
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Xianchi Dong: Harvard Medical School
Bo Zhao: Harvard Medical School
Roxana E. Iacob: Northeastern University
Jianghai Zhu: Harvard Medical School
Adem C. Koksal: Harvard Medical School
Chafen Lu: Harvard Medical School
John R. Engen: Northeastern University
Timothy A. Springer: Harvard Medical School

Nature, 2017, vol. 542, issue 7639, 55-59

Abstract: 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 αVβ6 binds 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.

Date: 2017
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DOI: 10.1038/nature21035

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