Monomeric (glycine-proline-hydroxyproline)10 repeat sequence is a partial agonist of the platelet collagen receptor glycoprotein VI.
We have previously reported that a triple-helical, collagen-related peptide (CRP; also known as CRP-XL) containing a glycine-proline-hydroxyproline (GPP*) repeat motif and cross-linked through cysteine residues at its N-terminus and C-terminus is a powerful stimulus of platelet aggregation and secretion through the surface receptor glycoprotein VI (GPVI). The activation of platelets is associated with tyrosine phosphorylation of the tyrosine kinase Syk and phospholipase C gamma2 (PLCgamma2). We now report that the non-cross-linked backbone of CRP, monomeric CRP (mCRP), stimulates the tyrosine phosphorylation of Syk and PLCgamma2 in platelets and induces the weak secretion of [3H]5-hydroxytryptamine ([3H]5-HT) and aggregation. The action of mCRP does not seem to be due to spontaneous cross-linking, because alkylation of the cysteine residues leads to an increase in activity. The tripeptide backbone of CRP, GPP*10 (in which P* represents hydroxyproline) also stimulates platelet shape change and the weak tyrosine phosphorylation of Syk and PLCgamma2, but is unable to induce aggregation or secretion. The monomeric peptides partly inhibit the release of [3H]5-HT by CRP, suggesting that they are partial agonists of the collagen receptor GPVI. These results demonstrate that GPP* present as a repeat motif is sufficient to activate the platelet collagen receptor GPVI but that the cross-linking of monomers brings about an increase in activity.
Asselin
J
J
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Knight
C G
CG
Farndale
R W
RW
Barnes
M J
MJ
Watson
S P
SP
D001792:Blood Platelets / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000819:agonists* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D038981:Receptors, Collagen; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D004792:Enzyme Precursors; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D010455:Peptides; D038981:Receptors, Collagen; D014443:Tyrosine; C036802:poly(hydroxyprolyl-prolyl-glycine)(10); D003094:Collagen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D010738:Type C Phospholipases; D051966:Phospholipase C gamma