Inhibition of ?IIb?3 Ligand Binding by an ?IIb Peptide that Clasps the Hybrid Domain to the ?I Domain of ?3.

ABSTRACT: Agonist-stimulated platelet activation triggers conformational changes of integrin ?IIb?3, allowing fibrinogen binding and platelet aggregation. We have previously shown that an octapeptide, p1YMESRADR8, corresponding to amino acids 313-320 of the ?-ribbon extending from the ?-propeller domain of ?IIb, acts as a potent inhibitor of platelet aggregation. Here we have performed in silico modelling analysis of the interaction of this peptide with ?IIb?3 in its bent and closed (not swing-out) conformation and show that the peptide is able to act as a substitute for the ?-ribbon by forming a clasp restraining the ?3 hybrid and ?I domains in a closed conformation. The involvement of species-specific residues of the ?3 hybrid domain (E356 and K384) and the ?1 domain (E297) as well as an intrapeptide bond (pE315-pR317) were confirmed as important for this interaction by mutagenesis studies of ?IIb?3 expressed in CHO cells and native or substituted peptide inhibitory studies on platelet functions. Furthermore, NMR data corroborate the above results. Our findings provide insight into the important functional role of the ?IIb ?-ribbon in preventing integrin ?IIb?3 head piece opening, and highlight a potential new therapeutic approach to prevent integrin ligand binding.

SUBMITTER: Lee WH 

PROVIDER: S-EPMC4557944 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature