Platelet factor 4 (CXCL4) seals blood clots by altering the structure of fibrin.
Platelet factor-4 (PF4/CXCL4) is an orphan chemokine released in large quantities in the vicinity of growing blood clots. Coagulation of plasma supplemented with a matching amount of PF4 results in a translucent jelly-like clot. Saturating amounts of PF4 reduce the porosity of the fibrin network 4.4-fold and decrease the values of the elastic and loss moduli by 31- and 59-fold, respectively. PF4 alters neither the cleavage of fibrinogen by thrombin nor the cross-linking of protofibrils by activated factor XIII but binds to fibrin and dramatically transforms the structure of the ensuing network. Scanning electron microscopy showed that PF4 gives rise to a previously unreported pattern of polymerization where fibrin assembles to form a sealed network. The subunits constituting PF4 form a tetrahedron having at its corners a RPRH motif that mimics (in reverse orientation) the Gly-His-Arg-Pro-amide peptides that co-crystallize with fibrin. Molecular modeling showed that PF4 could be docked to fibrin with remarkable complementarities and absence of steric clashes, allowing the assembly of irregular polymers. Consistent with this hypothesis, as little as 50 microm the QVRPRHIT peptide derived from PF4 affects the polymerization of fibrin.
Amelot
Aymeric A
AA
INSERM, U765, 75270 Paris Cedex 06, France.
Tagzirt
Madjid
M
Ducouret
Guylaine
G
Kuen
René Lai
RL
Le Bonniec
Bernard F
BF
D001777:Blood Coagulation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019281:Dimerization; D005337:Fibrin / Q000737:chemistry*; D005340:Fibrinogen / Q000737:chemistry; D005720:Gamma Rays; D006801:Humans; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D010978:Platelet Factor 4 / Q000737:chemistry / Q000502:physiology*; D011108:Polymers / Q000737:chemistry; D011485:Protein Binding; D055672:Static Electricity
D003432:Cross-Linking Reagents; D010455:Peptides; D011108:Polymers; D010978:Platelet Factor 4; D005337:Fibrin; D005340:Fibrinogen