5FFO

Integrin alpha V beta 6 in complex with pro-TGF-beta

Summary for 5FFO

• Entry DOI: 10.2210/pdb5ffo/pdb
• Related: 5FFG
• Descriptor: Integrin alpha-V, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION, ... (14 entities in total)
• Functional Keywords: integrin, tgf-beta, cell adhesion
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 368616.22

Authors

Dong, X.,Zhao, B.,Springer, T.A. (deposition date: 2015-12-18, release date: 2017-01-25, Last modification date: 2024-11-20)

Primary citation

Dong, X.,Zhao, B.,Iacob, R.E.,Zhu, J.,Koksal, A.C.,Lu, C.,Engen, J.R.,Springer, T.A.
Force interacts with macromolecular structure in activation of TGF-beta.
Nature, 542:55-59, 2017

PubMed 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 αβ 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.

PubMed: 28117447
DOI: 10.1038/nature21035

Experimental method

X-RAY DIFFRACTION (3.49 Å)