The atomic model of the human protective protein/cathepsin A suggests a structural basis for galactosialidosis

Gabrielle Rudenko, Erik Bonten, Wim G J Hol, Alessandra D'Azzo

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Human protective protein/cathepsin A (PPCA), a serine carboxypeptidase, forms a multienzyme complex with β-galactosidase and neuraminidase and is required for the intralysosomal activity and stability of these two glycosidases. Genetic lesions in PPCA lead to a deficiency of β- galactosidase and neuraminidase that is manifest as the autosomal recessive lysosomal storage disorder galactosialidosis. Eleven amino acid substitutions identified in mutant PPCAs from clinically different galactosialidosis patients have now been modeled in the three-dimensional structure of the wild-type enzyme. Of these substitutions, 9 are located in positions likely to alter drastically the folding and stability of the variant protein. In contrast, the other 2 mutations that are associated with a more moderate clinical outcome and are characterized by residual mature protein appeared to have a milder effect on protein structure. Remarkably, none of the mutations occurred in the active site or at the protein surface, which would have disrupted the catalytic activity or protective function. Instead, analysis of the 11 mutations revealed a substantive correlation between the effect of the amino acid substitution on the integrity of protein structure and the general severity of the clinical phenotype. The high incidence of PICA folding mutants in galactosialidosis reflects the fact that a single point mutation is unlikely to affect both the β-galactosidase and the neuraminidase binding sites of PPCA at the same time to produce the double glycosidase deficiency. Mutations in PICA that result in defective folding, however, disrupt every function of PPCA simultaneously.

Original languageEnglish (US)
Pages (from-to)621-625
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number2
DOIs
StatePublished - Jan 20 1998
Externally publishedYes

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Galactosidases
Cathepsin A
Mutation
Proteins
Glycoside Hydrolases
Neuraminidase
Amino Acid Substitution
Multienzyme Complexes
Protein Stability
Point Mutation
Neuraminidase deficiency with beta-galactosidase deficiency
human CTSA protein
Catalytic Domain
Membrane Proteins
Binding Sites
Phenotype
Incidence
Enzymes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The atomic model of the human protective protein/cathepsin A suggests a structural basis for galactosialidosis. / Rudenko, Gabrielle; Bonten, Erik; Hol, Wim G J; D'Azzo, Alessandra.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 2, 20.01.1998, p. 621-625.

Research output: Contribution to journalArticle

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