Structural determinants of integrin β-subunit specificity for latent TGF-β.
X.Dong,
N.E.Hudson,
C.Lu,
T.A.Springer.
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.
Links
