Latent TGF-β structure and activation

Shi, Minlong; Zhu, Jianghai; Wang, Rui; Chen, Xing; Mi, Lizhi; Walz, Thomas; Springer, Timothy A.

doi:10.1038/nature10152

Cited by 1,013TGF-β signaling in diseasesCell Adhesion Molecules ResearchProtease and Inhibitor Mechanisms

Latent TGF-β structure and activation

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Shi, Minlong, Zhu, Jianghai, Wang, Rui, Chen, Xing, Mi, Lizhi, Walz, Thomas, Springer, Timothy A.·2011·Nature

DOI 10.1038/nature10152PMC PMC4717672

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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 α(v) 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 α(v)β(6) 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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Authors: Shi, M., Zhu, J., Wang, R., Chen, X., Mi, L., Walz, T., & Springer, T. A.
Affiliations: Boston Children's Hospital (US)
Howard Hughes Medical Institute (US)
Corresponding author: Springer, Timothy A.
ORCID: Wang, Rui
Chen, Xing
Walz, Thomas
Springer, Timothy A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-06
Volume: 474
Issue: 7351
Pages: 343-349
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10152
PMC: PMC4717672
OpenAlex: W2051816002
Cited by: 1,013
References: 43
Citations by year: 2026: 51 · 2025: 62 · 2024: 84 · 2023: 70 · 2022: 100 · 2021: 88 · 2020: 72 · 2019: 53 · 2018: 67 · 2017: 63 · 2016: 73 · 2015: 70 · 2014: 54 · 2013: 44 · 2012: 50
FWCI: 20.66
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Howard Hughes Medical Institute
National Heart, Lung, and Blood Institute (P01HL103526)
National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: TGF-β1, latent TGF-beta, propeptide, latent TGF-beta binding protein, ITGAV, RGD motif, disulfide bonds, extracellular matrix, TGF-beta superfamily, growth factor activation
MeSH terms: Amino Acid Sequence, Animals, Antigens, Neoplasm, Cell Line, Camurati-Engelmann Syndrome, Multigene Family, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Oligopeptides, Swine, Integrins, Protein Structure, Tertiary, Receptors, Transforming Growth Factor beta, Crystallography, X-Ray, Amino Acid Motifs, Activins, Transforming Growth Factor beta1, Latent TGF-beta Binding Proteins, HEK293 Cells

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