8FXS

Crystal structure of human pro-TGF-beta2 in complex with Nb9

Summary for 8FXS

• Entry DOI: 10.2210/pdb8fxs/pdb
• Related: 8FXV
• Descriptor: Transforming growth factor beta-2 proprotein, Nanobody clone 9, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: tgf-b tgf-beta nanobody latent procomplex prodomain, cytokine
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 118437.68

Authors

Le, V.Q.,Springer, T.A. (deposition date: 2023-01-25, release date: 2023-06-21)

Primary citation

Le, V.Q.,Zhao, B.,Ramesh, S.,Toohey, C.,DeCosta, A.,Mintseris, J.,Liu, X.,Gygi, S.,Springer, T.A.
A specialized integrin-binding motif enables proTGF-beta 2 activation by integrin alpha V beta 6 but not alpha V beta 8.
Proc.Natl.Acad.Sci.USA, 120:e2304874120-e2304874120, 2023

PubMed Abstract: 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.

PubMed: 37279271
DOI: 10.1073/pnas.2304874120

Experimental method

X-RAY DIFFRACTION (3.15 Å)