Human cystatin C. role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase.

Department of Clinical Chemistry, University of Lund, University Hospital, Sweden.
Leucocyte elastase in catalytic amounts was observed to rapidly cleave the Val-10-Gly-11 bond of the human cysteine-proteinase inhibitor cystatin C at neutral pH. The resulting modified inhibitor had size and amino acid composition consistent with a cystatin C molecule devoid of the N-terminal Ser-1-Val-10 decapeptide. Leucocyte-elastase-modified cystatin C had more than 240-fold lower affinity than native cystatin C for papain. Removal of the N-terminal decapeptide of human cystatin C also decreased inhibition of human cathepsins B and L by three orders of magnitude, but decreased inhibition of cathepsin H by only 5-fold. A tripeptidyldiazomethane analogue of of the N-terminal portion of cystatin C was a good inhibitor of cathepsins B and L but a poor inhibitor of cathepsin H. It therefore appears that amino acid side chains of the N-terminal segment of cystatin C bind in the substrate-binding pockets of cathepsins B and L but not in those of cathepsin H. It is argued that the N-terminal cystatin C interaction with cathepsin B is physiologically important and hence that leucocyte elastase could have a function as a regulator of extracellular cysteine-proteinase inhibitory activity at sites of inflammation.
Mesh Terms:
Amino Acid Sequence, Cystatin C, Cystatins, Electrophoresis, Agar Gel, Electrophoresis, Polyacrylamide Gel, Escherichia coli, Humans, Kinetics, Leukocyte Elastase, Molecular Sequence Data, Molecular Weight, Pancreatic Elastase, Recombinant Proteins, Substrate Specificity
Biochem. J. Feb. 01, 1991; 273(0);621-6 [PUBMED:1996959]
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