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Proteolytic activation of human cathepsin A.

Abstract
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 3.4.16.5). 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.
AuthorsNilima Kolli, Scott C Garman
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 17 Pg. 11592-11600 (Apr 25 2014) ISSN: 1083-351X [Electronic] United States
PMID24599961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Cathepsin A
Topics
  • Cathepsin A (chemistry, metabolism)
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Proteolysis

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