Two‐step mechanism of inhibition of cathepsin B by cystatin C due to displacement of the proteinase occluding loop

FEBS Letters

Abrahamson, Magnus³  Björk, Ingemar²  Estrada, Sergio²  Nycander, Maria²  Mort, John S¹ 

[1]Joint Diseases Laboratory, Shriners Hospital for Children and the Department of Surgery, McGill University, Montreal, Que. H3G 1A6, Canada

[2]Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Center, Box 575, SE-751 23 Uppsala, Sweden

[3]Department of Clinical Chemistry, University of Lund, University Hospital, SE-221 85 Lund, Sweden

关键词: Cysteine proteinase;    Cysteine proteinase inhibitor;    Cathepsin;    Cystatin;    Kinetics;    H111W-cathepsin B;    a cathepsin B variant in which His-111 is replaced by Trp;   

DOI  :  10.1016/S0014-5793(97)01604-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Stopped-flow kinetics showed that the inhibition of the lysosomal cysteine proteinase, cathepsin B, by its endogenous inhibitor, cystatin C, occurs by a two-step mechanism, in which an initial, weak interaction is followed by a conformational change. The initial interaction most likely involves binding of the N-terminal region of the inhibitor to the proteinase. Considerable evidence indicates that the subsequent conformational change is due to the inhibitor displacing the occluding loop of the proteinase that partially obscures the active site. The presence of this loop, which allows the enzyme to function as an exopeptidase, thus complicates the inhibition mechanism, rendering cathepsin B much less susceptible than other cysteine proteinases to inhibition by cystatins.

【 授权许可】

Unknown