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

• Published in: The Journal of biological chemistry 2000-12, Vol.275 (48), p.37340-37346
• Main Authors: Knauer, D J, Majumdar, D, Fong, P C, Knauer, M F
• Format: Article
• Language: English
• Subjects: Amyloid beta-Protein Precursor; Carrier Proteins - pharmacology; Cell Line; Complement C1 Inactivator Proteins - pharmacology; Complement C1 Inhibitor Protein; Factor XIa - antagonists & inhibitors; Factor XIa - physiology; Heparin - pharmacology; Humans; Protease Nexins; Receptors, Cell Surface; Serine Proteinase Inhibitors - pharmacology; Serpin E2; Serpins - physiology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M003909200

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.