4MWS

Crystal structure of human PPCA (trigonal crystal form 1)

Summary for 4MWS

• Entry DOI: 10.2210/pdb4mws/pdb
• Related: 1IVY 4MWT
• Descriptor: Lysosomal protective protein, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)]2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: cathepsin a, glycoprotein, serine protease, carboxypeptidase, protective protein, n-linked glycosylation, proteolytically activated form, lysosomal enzyme, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 99565.27

Authors

Kolli, N.,Garman, S.C. (deposition date: 2013-09-25, release date: 2014-03-12, Last modification date: 2024-11-20)

Primary citation

Kolli, N.,Garman, S.C.
Proteolytic activation of human cathepsin A.
J.Biol.Chem., 289:11592-11600, 2014

PubMed 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.

PubMed: 24599961
DOI: 10.1074/jbc.M113.524280

Experimental method

X-RAY DIFFRACTION (2.8 Å)