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.
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Authors | Nilima Kolli, Scott C Garman |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 289
Issue 17
Pg. 11592-11600
(Apr 25 2014)
ISSN: 1083-351X [Electronic] United States |
PMID | 24599961
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
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Topics |
- Cathepsin A
(chemistry, metabolism)
- Electrophoresis, Polyacrylamide Gel
- Enzyme Activation
- Humans
- Models, Molecular
- Protein Conformation
- Proteolysis
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