Force interacts with macromolecular structure in activation of TGF-β

Dong, Xianchi; Zhao, Bo; Iacob, Roxana E.; Zhu, Jianghai; Koksal, Adem C.; Lu, Chafen; Engen, John R.; Springer, Timothy A.

doi:10.1038/nature21035

Force interacts with macromolecular structure in activation of TGF-β

Journal Article · Wed Jan 25 04:00:00 EST 2017 · Nature (London)

DOI:https://doi.org/10.1038/nature21035· OSTI ID:1357645

Dong, Xianchi ^[1]; Zhao, Bo ^[1]; Iacob, Roxana E. ^[2]; Zhu, Jianghai ^[1]; Koksal, Adem C. ^[1]; Lu, Chafen ^[1]; Engen, John R. ^[2]; Springer, Timothy A. ^[1]

Harvard Medical School, Boston, MA (United States)
Northeastern Univ., Boston, MA (United States)

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 α_Vβ₆ 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); Charles A. King Trust Postdoctoral Research Fellowship Program, Bank of America, N.A., Co-Trustee

OSTI ID:: 1357645

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7639 Vol. 542; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (27)

X-Ray Diffraction data from integrin alphaVbeta6 head, source of 5FFG structure Dong, Xianchi SBGrid Data Bank https://doi.org/10.15785/sbgrid/391	dataset	January 2016
X-Ray Diffraction data from integrin alphaVbeta6 head/pro-TGF-beta1 complex, source of 5FFO structure Dong, Xianchi SBGrid Data Bank https://doi.org/10.15785/sbgrid/392	dataset	January 2016
Investigating Monoclonal Antibody Aggregation Using a Combination of H/DX-MS and Other Biophysical Measurements Iacob, Roxana E.; Bou-Assaf, George M.; Makowski, Lee Journal of Pharmaceutical Sciences, Vol. 102, Issue 12 https://doi.org/10.1002/jps.23754	journal	December 2013
Hydrogen exchange mass spectrometry for the analysis of protein dynamics Wales, Thomas E.; Engen, John R. Mass Spectrometry Reviews, Vol. 25, Issue 1 https://doi.org/10.1002/mas.20064	journal	January 2005
An Assay for Transforming Growth Factor-β Using Cells Transfected with a Plasminogen Activator Inhibitor-1 Promoter-Luciferase Construct Abe, M.; Harpel, J. G.; Metz, C. N. Analytical Biochemistry, Vol. 216, Issue 2 https://doi.org/10.1006/abio.1994.1042	journal	February 1994
Strength of a Weak Bond Connecting Flexible Polymer Chains Evans, Evan; Ritchie, Ken Biophysical Journal, Vol. 76, Issue 5 https://doi.org/10.1016/S0006-3495(99)77399-6	journal	May 1999
Integrin inside-out signaling and the immunological synapse Springer, Timothy A.; Dustin, Michael L. Current Opinion in Cell Biology, Vol. 24, Issue 1 https://doi.org/10.1016/j.ceb.2011.10.004	journal	February 2012
Unchaining the beast; insights from structural and evolutionary studies on TGFβ secretion, sequestration, and activation Robertson, Ian B.; Rifkin, Daniel B. Cytokine & Growth Factor Reviews, Vol. 24, Issue 4 https://doi.org/10.1016/j.cytogfr.2013.06.003	journal	August 2013
Force-induced remodelling of proteins and their complexes Chen, Yun; Radford, Sheena E.; Brockwell, David J. Current Opinion in Structural Biology, Vol. 30 https://doi.org/10.1016/j.sbi.2015.02.001	journal	February 2015
Latent TGF-β structure and activation Shi, Minlong; Zhu, Jianghai; Wang, Rui Nature, Vol. 474, Issue 7351 https://doi.org/10.1038/nature10152	journal	June 2011
Coordinated integrin activation by actin-dependent force during T-cell migration Nordenfelt, Pontus; Elliott, Hunter L.; Springer, Timothy A. Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms13119	journal	October 2016
Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin Van Agthoven, Johannes F.; Xiong, Jian-Ping; Alonso, José Luis Nature Structural & Molecular Biology, Vol. 21, Issue 4 https://doi.org/10.1038/nsmb.2797	journal	March 2014
Structural determinants of integrin β-subunit specificity for latent TGF-β Dong, Xianchi; Hudson, Nathan E.; Lu, Chafen Nature Structural & Molecular Biology, Vol. 21, Issue 12 https://doi.org/10.1038/nsmb.2905	journal	November 2014
Protein structure alignment beyond spatial proximity Wang, Sheng; Ma, Jianzhu; Peng, Jian Scientific Reports, Vol. 3, Issue 1 https://doi.org/10.1038/srep01448	journal	March 2013
Structure of bone morphogenetic protein 9 procomplex Mi, Li-Zhi; Brown, Christopher T.; Gao, Yijie Proceedings of the National Academy of Sciences https://doi.org/10.1073/pnas.1501303112	journal	March 2015
Intact α _IIb β ₃ Integrin Is Extended after Activation as Measured by Solution X-ray Scattering and Electron Microscopy Eng, Edward T.; Smagghe, Benoit J.; Walz, Thomas Journal of Biological Chemistry, Vol. 286, Issue 40 https://doi.org/10.1074/jbc.M111.275107	journal	August 2011
Crystal structure of α5β1 integrin ectodomain: Atomic details of the fibronectin receptor Nagae, Masamichi; Re, Suyong; Mihara, Emiko The Journal of Cell Biology, Vol. 197, Issue 1 https://doi.org/10.1083/jcb.201111077	journal	March 2012
Complete integrin headpiece opening in eight steps Zhu, Jieqing; Zhu, Jianghai; Springer, Timothy A. The Journal of Cell Biology, Vol. 201, Issue 7 https://doi.org/10.1083/jcb.201212037	journal	June 2013
An internal ligand-bound, metastable state of a leukocyte integrin, α _X β ₂ Sen, Mehmet; Yuki, Koichi; Springer, Timothy A. The Journal of Cell Biology, Vol. 203, Issue 4 https://doi.org/10.1083/jcb.201308083	journal	November 2013
Fibronectins, Their Fibrillogenesis, and In Vivo Functions Schwarzbauer, J. E.; DeSimone, D. W. Cold Spring Harbor Perspectives in Biology, Vol. 3, Issue 7 https://doi.org/10.1101/cshperspect.a005041	journal	May 2011
Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins Robertson, Ian B.; Rifkin, Daniel B. Cold Spring Harbor Perspectives in Biology, Vol. 8, Issue 6 https://doi.org/10.1101/cshperspect.a021907	journal	June 2016
Structural Biology and Evolution of the TGF-β Family Hinck, Andrew P.; Mueller, Thomas D.; Springer, Timothy A. Cold Spring Harbor Perspectives in Biology, Vol. 8, Issue 12 https://doi.org/10.1101/cshperspect.a022103	journal	September 2016
PRIMUS: a Windows PC-based system for small-angle scattering data analysis Konarev, Petr V.; Volkov, Vladimir V.; Sokolova, Anna V. Journal of Applied Crystallography, Vol. 36, Issue 5, p. 1277-1282 https://doi.org/10.1107/S0021889803012779	journal	September 2003
CRYSOL – a Program to Evaluate X-ray Solution Scattering of Biological Macromolecules from Atomic Coordinates Svergun, D.; Barberato, C.; Koch, M. H. J. Journal of Applied Crystallography, Vol. 28, Issue 6 https://doi.org/10.1107/S0021889895007047	journal	December 1995
Crystal Structure of the Extracellular Segment of Integrin alpha Vbeta 3 in Complex with an Arg-Gly-Asp Ligand Xiong, J. -P. Science, Vol. 296, Issue 5565 https://doi.org/10.1126/science.1069040	journal	March 2002
Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment Janssens, K. Journal of Medical Genetics, Vol. 43, Issue 1 https://doi.org/10.1136/jmg.2005.033522	journal	May 2005
A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13 Zhou, Minyun; Dong, Xianchi; Baldauf, Carsten Blood, Vol. 117, Issue 17 https://doi.org/10.1182/blood-2010-11-321596	journal	April 2011

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Von einer Helix zu einem kleinen Ring: Metadynamik-inspirierte, selektive Liganden für αvβ6-Integrin Di Leva, Francesco Saverio; Tomassi, Stefano; Di Maro, Salvatore Angewandte Chemie, Vol. 130, Issue 44 https://doi.org/10.1002/ange.201803250	journal	May 2018
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Mechanoreciprocity in cell migration van Helvert, Sjoerd; Storm, Cornelis; Friedl, Peter Nature Cell Biology, Vol. 20, Issue 1 https://doi.org/10.1038/s41556-017-0012-0	journal	December 2017
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TGF-β1 Signaling and Tissue Fibrosis Kim, Kevin K.; Sheppard, Dean; Chapman, Harold A. Cold Spring Harbor Perspectives in Biology, Vol. 10, Issue 4 https://doi.org/10.1101/cshperspect.a022293	journal	April 2017
Structural consequences on transforming growth factor beta-1 activation from near-therapeutic X-ray doses Stachowski, Timothy R.; Grant, Thomas D.; Snell, Edward H. Acta Crystallographica Section A Foundations and Advances, Vol. 75, Issue a1 https://doi.org/10.1107/s0108767319097708	journal	July 2019
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Structural consequences of transforming growth factor beta-1 activation from near-therapeutic X-ray doses Stachowski, Timothy; Grant, Thomas D.; Snell, Edward H. International Union of Crystallography (IUCr) https://doi.org/10.1107/s1600577519005113/gm5059sup1.pdf	text	January 2019
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