A tripeptide mimetic of von Willebrand factor residues 981-983 enhances platelet adhesion to fibrinogen by signaling through integrin alpha(IIb)beta3.
BACKGROUND
RGD is a major recognition sequence for ligands of platelet alpha(IIb)beta3.


OBJECTIVE
To identify potential binding sites for alpha(IIb)beta3 apart from RGD, we screened phage display libraries by blocking the enrichment of RGD-containing phages with a GRGDS peptide and identified a novel integrin recognition tripeptide sequence, VPW.


RESULTS
Platelets adhered to an immobilized cyclic VPW containing peptide in a alpha(IIb)beta3-dependent manner; platelets and alpha(IIb)beta3-expressing CHO cells adhered faster to immobilized alpha(IIb)beta3-ligands in the presence of soluble VPW. In platelets adhering to fibrinogen, VPW accelerated the activation of the tyrosine kinase Syk which controls cytoskeletal rearrangements. In alpha(IIb)beta3-expressing CHO cells, VPW induced a faster formation of stress fibers. Sequence alignment positioned VPW to V980-P981-W982 in the von Willebrand factor (vWf) A-3 domain. In blood from a vWf-deficient individual, VPW increased platelet adhesion to fibrinogen but not to collagen under flow and rescued the impaired adhesion to vWf deficient in A-3.


CONCLUSIONS
These data reveal a VPW sequence that contributes to alpha(IIb)beta3 activation in in vitro experiments. Whether the V980-P981-W982 sequence in vWf shows similar properties under in vivo conditions remains to be established.
Litjens
P E M H
PE
Laboratory for Thrombosis and Haemostasis, Department of Haematology, UMCU, and Institute for Biomembranes, Utrecht University, Utrecht, The Netherlands.
Van Willigen
G
G
Weeterings
C
C
Ijsseldijk
M J W
MJ
Van Lier
M
M
Koivunen
E
E
Gahmberg
C G
CG
Akkerman
J W N
JW
D000595:Amino Acid Sequence; D001665:Binding Sites; D001792:Blood Platelets; D004792:Enzyme Precursors / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014842:von Willebrand Diseases / Q000097:blood; D014841:von Willebrand Factor / Q000031:analogs & derivatives* / Q000737:chemistry / Q000502:physiology
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014841:von Willebrand Factor; D005340:Fibrinogen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase