Functional and structural similarities between protease nexin I and C1 inhibitor.
Protease nexin I is a proteinase inhibitor that is secreted by human fibroblasts and forms stable complexes with certain serine proteinases; the complexes then bind to the fibroblasts and are rapidly internalized and degraded. In this report, we show that this inhibitor, which is present in very low concentrations in plasma, has functional and structural similarities to C1 inhibitor, an abundant proteinase inhibitor in plasma. Both inhibitors complex and inactivate certain proteinases that previously were known to rapidly react only with C1 inhibitor. Kinetic inhibition studies show that protease nexin I inhibits Factor XIIa and plasma kallikrein with second-order rate constants of 2.3 x 10(3) and 2.5 x 10(5) M-1 s-1, respectively, which are similar to the rate constants for inhibition of these proteinases by C1 inhibitor. Protease nexin I inhibits C1s about one-tenth as rapidly as does C1 inhibitor. Alignment of the amino acid sequences of protease nexin I and C1 inhibitor shows that these proteins have similarity at their reactive centers (from sites P7 to P1). The remaining regions of the two proteins share much less similarity. In contrast to protease nexin I, C1 inhibitor is not secreted by human fibroblasts. Although 125I-C1s-protease nexin I complexes readily bind to human fibroblasts, binding of 125I-C1s-C1 inhibitor complexes or other 125I-proteinase-C1-inhibitor complexes to these cells is not detectable. Thus, protease nexin I and C1 inhibitor may control some common regulatory proteinases in the extravascular and vascular compartments, respectively.
Van Nostrand
W E
WE
Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine 92717.
McKay
L D
LD
Baker
J B
JB
Cunningham
D D
DD
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor; D001665:Binding Sites; D002352:Carrier Proteins / Q000302:isolation & purification / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010447:Peptide Hydrolases / Q000378:metabolism; D058255:Protease Nexins; D011485:Protein Binding; D011956:Receptors, Cell Surface; D013329:Structure-Activity Relationship
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D003174:Complement C1 Inactivator Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D010447:Peptide Hydrolases