Proteolytic activation of human cathepsin A

J Biol Chem. 2014 Apr 25;289(17):11592-11600. doi: 10.1074/jbc.M113.524280. Epub 2014 Mar 5.


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 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.

Keywords: Glycoprotein Structure; Lysosomal Glycoproteins; Protease; Proteolytic Enzymes; X-ray Crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cathepsin A / chemistry
  • Cathepsin A / metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Proteolysis


  • Cathepsin A