Latent TGF-β structure and activation

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Abstract

Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of αv integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between αvβ6 integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a ‘straitjacket’ that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.

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Figure 1: Architecture of proTGF-β1.
Figure 2: The TGF-β family.
Figure 3: Shielding from receptor binding.
Figure 4: ProTGF-β1 complexes with LTBP and α v β 6 integrin, and activation of TGF-β.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

X-ray structures have been deposited in the Protein Data Bank under the accession number 3RJR.

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Acknowledgements

We thank P. Sun for porcine TGF-β1 cDNA, K. Koli for human TGF-β1 and LTBP1 cDNAs, D. Rifkin for human LTBP1 cDNA and transformed mink lung epithelial cells, and the staff of the Advanced Photon Source General Medical Sciences and National Cancer Institute (APS GM/CA-CAT) beamline 23-ID.

Author information

M.S. cloned, expressed and purified proTGF-β1, crystallized the protein, collected and processed X-ray data, refined and analysed the structure, designed and performed biochemical assays and wrote the paper. J.Z. collected and processed X-ray data, refined and analysed the structure and performed electron microscopy studies. R.W. designed and performed TGF-β1 assays. X.C. performed electron microscopy studies. L.M. processed X-ray data. T.W. provided electron microscopy supervision. T.A.S. designed and supervised the project, refined and analysed the structure and wrote the paper.

Correspondence to Timothy A. Springer.

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Shi, M., Zhu, J., Wang, R. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011) doi:10.1038/nature10152

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