Novel peptides derived from a region of local homology between uteroglobin and lipocortin-1 inhibit platelet aggregation and secretion.
The active site for uteroglobin inhibition of phospholipase A2 has been localized to a nonapeptide (P1) which is partially homologous to a nonapeptide (P2) in lipocortin, which also inhibits phospholipase A2. P1 and P2 share an identical tetrapeptide (P4) which is required for inhibition, although P4 alone does not inhibit this enzyme. We found the mechanism of inhibition of platelet aggregation and secretion by the nonapeptides and P4 varied depending on whether platelets were thrombin- or ADP-activated. All three peptides decrease thrombin esterolytic activity and thereby inhibit thrombin-induced platelet activation. P1 decreases ADP-induced aggregation and serotonin secretion by inhibiting phospholipase A2 whereas P4 decreases only aggregation by blocking fibrinogen binding to activated platelets. The P4 sequence in P1 may affect the interaction of P1 with platelets since the presence of P4 potentiates P1 inhibition of platelet activation.
Vostal
J G
JG
Clinical Hematology Branch, National Institute of Diabetes, Digestive and Kidney Disease, Bethesda, Maryland 20892.
Mukherjee
A B
AB
Miele
L
L
Shulman
N R
NR
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D017302:Annexins; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000138:chemical synthesis / Q000494:pharmacology*; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D014598:Uteroglobin / Q000138:chemical synthesis / Q000494:pharmacology*
D017302:Annexins; D001095:Arachidonic Acids; D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D014598:Uteroglobin; D010740:Phospholipases