Structural determinants of integrin β-subunit specificity for latent TGF-β.
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.
1] Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Xianchi
X
Dong
1] Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Nathan E
NE
Hudson
1] Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Chafen
C
Lu
1] Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Timothy A
TA
Springer
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment; D053773:Transforming Growth Factor beta1 / Q000737:chemistry / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000737:chemistry / Q000378:metabolism*
D000951:Antigens, Neoplasm; D016023:Integrins; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; C073878:integrin alphavbeta6