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A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8

Activation of latent transforming growth factor (TGF)-β2 is incompletely understood. Unlike TGF-β1 and β3, the TGF-β2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-β2 contains a...

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Autores principales: Le, Viet Q., Zhao, Bo, Ramesh, Siddanth, Toohey, Cameron, DeCosta, Adam, Mintseris, Julian, Liu, Xinyue, Gygi, Steven, Springer, Timothy A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268255/
https://www.ncbi.nlm.nih.gov/pubmed/37279271
http://dx.doi.org/10.1073/pnas.2304874120
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author Le, Viet Q.
Zhao, Bo
Ramesh, Siddanth
Toohey, Cameron
DeCosta, Adam
Mintseris, Julian
Liu, Xinyue
Gygi, Steven
Springer, Timothy A.
author_facet Le, Viet Q.
Zhao, Bo
Ramesh, Siddanth
Toohey, Cameron
DeCosta, Adam
Mintseris, Julian
Liu, Xinyue
Gygi, Steven
Springer, Timothy A.
author_sort Le, Viet Q.
collection PubMed
description Activation of latent transforming growth factor (TGF)-β2 is incompletely understood. Unlike TGF-β1 and β3, the TGF-β2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-β2 contains a related but divergent 13-residue integrin-recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin αVβ6 but not αVβ8. Both classes of motifs compete for the same binding site in αVβ6. Multiple changes in the longer motif underlie its specificity. ProTGF-β2 structures define interesting differences from proTGF-β1 and the structural context for activation by αVβ6. Some integrin-independent activation is also seen for proTGF-β2 and even more so for proTGF-β3. Our findings have important implications for therapeutics to αVβ6 in clinical trials for fibrosis, in which inhibition of TGF-β2 activation has not been anticipated.
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spelling pubmed-102682552023-12-06 A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8 Le, Viet Q. Zhao, Bo Ramesh, Siddanth Toohey, Cameron DeCosta, Adam Mintseris, Julian Liu, Xinyue Gygi, Steven Springer, Timothy A. Proc Natl Acad Sci U S A Biological Sciences Activation of latent transforming growth factor (TGF)-β2 is incompletely understood. Unlike TGF-β1 and β3, the TGF-β2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-β2 contains a related but divergent 13-residue integrin-recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin αVβ6 but not αVβ8. Both classes of motifs compete for the same binding site in αVβ6. Multiple changes in the longer motif underlie its specificity. ProTGF-β2 structures define interesting differences from proTGF-β1 and the structural context for activation by αVβ6. Some integrin-independent activation is also seen for proTGF-β2 and even more so for proTGF-β3. Our findings have important implications for therapeutics to αVβ6 in clinical trials for fibrosis, in which inhibition of TGF-β2 activation has not been anticipated. National Academy of Sciences 2023-06-06 2023-06-13 /pmc/articles/PMC10268255/ /pubmed/37279271 http://dx.doi.org/10.1073/pnas.2304874120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Le, Viet Q.
Zhao, Bo
Ramesh, Siddanth
Toohey, Cameron
DeCosta, Adam
Mintseris, Julian
Liu, Xinyue
Gygi, Steven
Springer, Timothy A.
A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8
title A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8
title_full A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8
title_fullStr A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8
title_full_unstemmed A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8
title_short A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8
title_sort specialized integrin-binding motif enables protgf-β2 activation by integrin αvβ6 but not αvβ8
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268255/
https://www.ncbi.nlm.nih.gov/pubmed/37279271
http://dx.doi.org/10.1073/pnas.2304874120
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