Inhibitory and antiadhesive properties of human kininogens.
Each of 11 exons of the human kininogen gene has the potential to code for different functional activities of the molecule in both bradykinin formation and interactions with platelets, neutrophils and endothelial cells. Our recent studies have localized amino acid sequences in exon 4 product and exon 5 product in domain 2, which bind and inhibit platelet calpain, respectively. Furthermore, we have shown that the exon 7 product expressed in domain 3 contains a decapeptide which interacts with thrombospondin on activated platelets, and a distinct septapeptide which inhibits thrombin-induced activation of platelets. Exon 8 and 9 products cooperate to inhibit cathepsins B and H. Domain 3 also contains a cell binding site for neutrophils, as does domain 5. Fine mapping of both cell binding domains has been performed by several groups of investigators for neutrophils, endothelial cells and platelets. The cell binding domain in D5 overlaps with the anionic surface binding subdomain of D5. The monomeric structure of kininogen assures that it will function as an antiadhesive protein, unlike dimeric fibrinogen. High molecular weight kininogen competes with fibrinogen binding to neutrophils and platelets. We have also fine mapped the domains for binding of kininogen (domain 6) to prekallikrein 'apple' domains 1 and 4. Kininogens can serve as proinflammatory proteins by releasing bradykinin, but cleaved kininogens exhibit antiadhesive and anti-inflammatory properties.
Colman
R W
RW
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
D000595:Amino Acid Sequence; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005340:Fibrinogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007704:Kininogens / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology
D007704:Kininogens; D005340:Fibrinogen; D002154:Calpain