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Structural determinants of integrin ?-subunit specificity for latent TGF-?.

ABSTRACT: Eight integrin ?-? 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 ?V?6 binds with high affinity to a RGDLXXL/I motif within the prodomains of TGF-?1 and TGF-?3. The LXXL/I motif forms an amphipathic ?-helix that binds in a hydrophobic pocket in the ?6 subunit. Elucidation of the basis for ligand binding specificity by the integrin ? subunit reveals contributions by three different ?I-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 ? subunit in integrin evolution, thus suggesting a paradigmatic role in overall ?-subunit function.

SUBMITTER: Dong X

PROVIDER: S-EPMC4717663 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Dong Xianchi X Hudson Nathan E NE Lu Chafen C Springer Timothy A TA

Nature structural & molecular biology 20141110 12

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 ...[more]

PMID: 25383667

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