SERPIN regulation of factor XIa. The novel observation that protease nexin 1 in the presence of heparin is a more potent inhibitor of factor XIa than C1 inhibitor.
In the present studies we have made the novel observation that protease nexin 1 (PN1), a member of the serine protease inhibitor (SERPIN) superfamily, is a potent inhibitor of the blood coagulation Factor XIa (FXIa). The inhibitory complexes formed between PN1 and FXIa are stable when subjected to reducing agents, SDS, and boiling, a characteristic of the acyl linkage formed between SERPINs and their cognate proteases. Using a sensitive fluorescence-quenched peptide substrate, the K(assoc) of PN1 for FXIa was determined to be 7.9 x 10(4) m(-)(1) s(-)(1) in the absence of heparin. In the presence of heparin, this rate was accelerated to 1.7 x 10(6), M(-)(1) s(-)(1), making PN1 a far better inhibitor of FXIa than C1 inhibitor, which is the only other SERPIN known to significantly inhibit FXIa. FXIa-PN1 complexes are shown to be internalized and degraded by human fibroblasts, most likely via the low density lipoprotein receptor-related protein (LRP), since degradation was strongly inhibited by the LRP agonist, receptor-associated protein. Since FXIa proteolytically modifies the amyloid precursor protein, this observation may suggest an accessory role for PN1 in the pathobiogenesis of Alzheimer's disease.
Knauer
D J
DJ
Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, California 92627, USA.
Majumdar
D
D
Fong
P C
PC
Knauer
M F
MF
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins / Q000494:pharmacology*; D002460:Cell Line; D003174:Complement C1 Inactivator Proteins / Q000494:pharmacology*; D050718:Complement C1 Inhibitor Protein; D015945:Factor XIa / Q000037:antagonists & inhibitors / Q000502:physiology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D058258:Serpin E2; D015843:Serpins / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D015842:Serine Proteinase Inhibitors; D058258:Serpin E2; D015843:Serpins; D006493:Heparin; D015945:Factor XIa