An unusual specificity in the activation of neutrophil serine proteinase zymogens.
The majority of proteinases exist as zymogens whose activation usually results from a single proteolytic event. Two notable exceptions to this generalization are the serine proteinases neutrophil elastase (HNE) and cathepsin G (cat G), proteolytic enzymes of human neutrophils that are apparently fully active in their storage granules. On the basis of amino acid sequences inferred from the gene and cDNAs encoding these enzymes, it is likely that both are synthesized as precursors containing unusual C-terminal and N-terminal peptide extensions absent from the mature proteins. We have used biosynthetic radiolabeling and radiosequencing techniques to identify the kinetics of activation of both proteinases in the promonocyte-like cell line U937. We find that both N- and C-terminal extensions are removed about 90 min after the onset of synthesis, resulting in the activation of the proteinases. HNE and cat G are, therefore, transiently present as zymogens, presumably to protect the biosynthetic machinery of the cell from adventitious proteolysis. Activation results from cleavage following a glutamic acid residue to give an activation specificity opposite to those of almost all other serine proteinase zymogens, but shared, possibly, by the "granzyme" group of related serine proteinases present in the killer granules of cytotoxic T-lymphocytes and rat mast cell proteinase II.
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 / Q000097:blood*; D002460:Cell Line; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000097:blood*; D007553:Isotope Labeling; D007700:Kinetics; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000097:blood*; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000097:blood*
D004792:Enzyme Precursors; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase