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Structural determinants of integrin β-subunit specificity for latent TGF-β

Nature Structural & Molecular Biology volume 21, pages 10911096 (2014) | Download Citation

Abstract

Eight integrin α-β heterodimers recognize ligands with an Arg-Gly-Asp (RGD) motif. However, the structural mechanism by which integrins differentiate among extracellular proteins with RGD motifs is not understood. Here, crystal structures, mutations and peptide-affinity measurements show that αVβ6 binds with high affinity to a RGDLXXL/I motif within the prodomains of TGF-β1 and TGF-β3. The LXXL/I motif forms an amphipathic α-helix that binds in a hydrophobic pocket in the β6 subunit. Elucidation of the basis for ligand binding specificity by the integrin β subunit reveals contributions by three different βI-domain loops, which we designate specificity-determining loops (SDLs) 1, 2 and 3. Variation in a pair of single key residues in SDL1 and SDL3 correlates with the variation of the entire β subunit in integrin evolution, thus suggesting a paradigmatic role in overall β-subunit function.

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Acknowledgements

This work was supported by US National Institutes of Health grant NIH P01HL103526 (T.A.S.).

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Affiliations

  1. Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Xianchi Dong
    • , Nathan E Hudson
    • , Chafen Lu
    •  & Timothy A Springer
  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.

    • Xianchi Dong
    • , Nathan E Hudson
    • , Chafen Lu
    •  & Timothy A Springer

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Contributions

X.D. contributed to research design, carried out experiments, analyzed data and wrote the manuscript. N.E.H. helped to analyze the data and prepare the manuscript. C.L. contributed research design. T.A.S. conceived the experimental design, analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy A Springer.

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DOI

https://doi.org/10.1038/nsmb.2905

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