The structural basis for neutrophil inactivation of C1 inhibitor.
Limited proteolysis of C1 inhibitor (C1-INH) by neutrophil elastase, Pseudomonas elastase and snake venoms resulted in initial cleavage within the molecule's N-terminus followed by further cleavage within the molecule's C-terminally placed reactive centre. N-Terminal proteolysis occurred at peptide bonds 14-15, 36-37 and 40-41. This had no effect on either the inhibitory activity or the heat-stability of C1-INH. Proteolysis within the reactive centre occurred at peptide bonds 439-440, 440-441, 441-442 and 442-443. Cleavage at any one of these sites inactivated C1-INH and conferred enhanced heat-stability upon a previously heat-labile molecule. Released neutrophil proteinases also cleaved and inactivated C1-INH, suggesting that they may physiologically regulate C1-INH during inflammatory episodes.
Pemberton
P A
PA
Department of Haematological Medicine, University of Cambridge Medical School, U.K.
Harrison
R A
RA
Lachmann
P J
PJ
Carrell
R W
RW
D000818:Animals; D001665:Binding Sites; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides; D011549:Pseudomonas; D012910:Snake Venoms / Q000378:metabolism / Q000494:pharmacology*
D003174:Complement C1 Inactivator Proteins; D010455:Peptides; D012910:Snake Venoms; D010196:Pancreatic Elastase