Protein inhibitors form complexes with procathepsin L and augment cleavage of the propeptide.
The proregion fits tightly into the active site in the tertiary structure of procathepsin L and prevents its activity. We show that complexes between enzyme precursor and its endogenous protein inhibitors-the cystatins-can be formed without prior proteolytic removal of the propeptide. Complexes between cystatins and procathepsin L are formed at acidic pH and their formation is facilitated by acidic oligosaccharides. Binding of the inhibitor to the proenzyme is reversible and the slow dissociation of complex around neutral pH may serve as a pool for the sustained release of the enzyme. Formation of the complex between cystatin and procathepsin L increases the susceptibility of the proregion to proteolytic cleavage. This process may constitute an alternative mechanism of formation of the complex between enzyme and inhibitor without prior activation of the proenzyme.
Majerle
Andreja
A
Laboratory of Biotechnology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia.
Jerala
Roman
R
D019943:Amino Acid Substitution; D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000378:metabolism / Q000494:pharmacology; D055312:Cystatin A; D015891:Cystatins / Q000378:metabolism* / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016264:Dextran Sulfate / Q000378:metabolism / Q000494:pharmacology; D004792:Enzyme Precursors / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009154:Mutation; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D012694:Serine / Q000378:metabolism; D013696:Temperature; D014357:Trypsin / Q000378:metabolism / Q000494:pharmacology
D055312:Cystatin A; D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D012694:Serine; C026407:CSTA protein, human; D002809:Chondroitin Sulfates; D016264:Dextran Sulfate; D002403:Cathepsins; D014357:Trypsin; C063905:procathepsin L; D056668:Cathepsin L