Zymogen activation specificity and genomic structures of human neutrophil elastase and cathepsin G reveal a new branch of the chymotrypsinogen superfamily of serine proteinases.
On the basis of amino acid sequences inferred from the genes encoding human neutrophil elastase and cathepsin G, it is likely that both are synthesized as precursors containing N- and C-terminal peptide extensions. We show that these extensions are removed about 90 min after onset of synthesis of these proteins in the U937 cell line. Removal of these extensions causes activation of the proteinases, and it is likely that the N-terminal extension of each enzyme serves as a zymogen activation peptide. Elastase and cathepsin G are, therefore, transiently present as zymogens, presumably to protect the biosynthetic machinery of the cell from adventitious proteolysis. Zymogen activation results from cleavage following a glutamic acid residue, a specificity opposite to most other serine proteinase zymogens. The specificity is likely to be shared, however, by neutrophil proteinase 3, rat mast cell proteinase II, and most members of the granzyme group of proteinases present in cytotoxic T-lymphocyte granules. The conservation in zymogen activation specificity between these leukocyte proteinase homologs is mirrored by the preservation of a discrete genomic organization. This suggests that most of the leukocyte serine proteinases evolved from a common ancestor distinct from the main branches of the chymotrypsinogen superfamily of serine proteinases.
Salvesen
G
G
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.
Enghild
J J
JJ
D000595:Amino Acid Sequence; D056649:Cathepsin G; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002919:Chymotrypsinogen / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D005810:Multigene Family; D010196:Pancreatic Elastase / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
D004792:Enzyme Precursors; D002919:Chymotrypsinogen; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase