Proteolytic activation of human cathepsin A.
Publication Type:Journal Article
Source:J Biol Chem, Volume 289, Issue 17, p.11592-600 (2014)
Keywords:Cathepsin A, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Humans, Models, Molecular, Protein Conformation, Proteolysis
<p>Galactosialidosis is a human lysosomal storage disease caused by deficiency in the multifunctional lysosomal protease cathepsin A (also known as protective protein/cathepsin A, PPCA, catA, HPP, and CTSA; EC 220.127.116.11). Previous structural work on the inactive precursor human cathepsin A (zymogen) led to a two-stage model for activation, where proteolysis of a 1.6-kDa excision peptide is followed by a conformational change in a blocking peptide occluding the active site. Here we present evidence for an alternate model of activation of human cathepsin A, needing only cleavage of a 3.3-kDa excision peptide to yield full enzymatic activity, with no conformational change required. We present x-ray crystallographic, mass spectrometric, amino acid sequencing, enzymatic, and cellular data to support the cleavage-only activation model. The results clarify a longstanding question about the mechanism of cathepsin A activation and point to new avenues for the design of mechanism-based inhibitors of the enzyme. </p>