An echistatin C-terminal peptide activates GPIIbIIIa binding to fibrinogen, fibronectin, vitronectin and collagen type I and type IV.
Integrin binding to proteins often involves recognition of domains containing the arginine-glycine-aspartate (RGD) motif. Different binding affinities and specificities of the integrin-ligand protein interactions involve additional protein domains. The n.m.r. structure of the snake-venom protein echistatin suggested that the C-terminal portion of the molecule might be important, in addition to the RGD domain, in binding to the integrin glycoprotein IIbIIIa (GPIIbIIIa) [Saudek, Atkinson and Pelton (1991) Biochem. 30, 7369-7372]. The synthetic C-terminal peptide, echistatin-(40-49), PRNPHKGPAT, (1) inhibited binding of GPIIbIIIa to immobilized echistatin (IC50 3-6 mM), but did not inhibit binding of GPIIbIIIa to immobilized fibrinogen (up to 5 mM peptide), (2) activated GPIIbIIIa binding to fibronectin and vitronectin, usual ligands for the activated integrin, (3) activated binding of GPIIbIIIa to collagen type I and type IV, proteins not usually regarded as ligands for the integrin, and (4) stimulated 125I-fibrinogen binding by human platelets. These findings argue for an interaction of this non-RGD domain in echistatin with GPIIbIIIa, leading to activation of the integrin and extension of the ligand specificity to include immobilized collagen.
Wright
P S
PS
Marion Merrell Dow Research Institute, Cincinnati, OH 45215-6300.
Saudek
V
V
Owen
T J
TJ
Harbeson
S L
SL
Bitonti
A J
AJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005340:Fibrinogen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D010455:Peptides; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D014757:Viper Venoms / Q000494:pharmacology*; D019096:Vitronectin
D005353:Fibronectins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D014757:Viper Venoms; D019096:Vitronectin; C057986:echistatin; D005340:Fibrinogen; D003094:Collagen