title: Clusterin is a specific stabilizer and liberator of extracellular cathepsin K.
abstract: The cysteine peptidase cathepsin K is a major player in extracellular proteolysis. Here we describe the identification of the multifunctional extracellular chaperone clusterin as a cathepsin K-binding protein. Clusterin increases the stability of cathepsin K in dilute solution and in the presence of high protein concentration. It does not alter the activity of the enzyme but acts as a liberator by preventing substrate inhibition. Kinetic measurements show that clusterin binds cathepsin K with high affinity (K(d) = 0.5-0.6 nM). Altogether these results provide novel insights into the mechanisms involved in the fine-tuning of cysteine cathepsin activity in the extracellular space.
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia. marko.novinec@fkkt.uni-lj.si
authors.forename: Marko
authors.initials: M
authors.lastname: Novinec
authors.forename: Brigita
authors.initials: B
authors.lastname: Lenarčič
authors.forename: Antonio
authors.initials: A
authors.lastname: Baici
mesh_terms: D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002846:Chromatography, Affinity; D051152:Clusterin / Q000378:metabolism*; D003374:Coumarins / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism; D004795:Enzyme Stability; D004800:Enzymes, Immobilized / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005110:Extracellular Space; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D009994:Osmolar Concentration; D059748:Proteolysis; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D004800:Enzymes, Immobilized; D008024:Ligands; D011994:Recombinant Proteins; C021159:benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide; C534130:CTSK protein, human; D056657:Cathepsin K