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The 1.9 Å Structure of Human α- N -Acetylgalactosaminidase: The Molecular Basis of Schindler and Kanzaki Diseases

Journal of Molecular Biology, ISSN: 0022-2836, Vol: 393, Issue: 2, Page: 435-447
2009
  • 49
    Citations
  • 0
    Usage
  • 72
    Captures
  • 4
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    49
  • Captures
    72
  • Mentions
    4
    • References
      4
      • Wikipedia
        4

Article Description

α- N -acetylgalactosaminidase (α-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal α- N -acetylgalactosamine residues from glycopeptides and glycolipids. In humans, a deficiency of α-NAGAL activity results in the lysosomal storage disorders Schindler disease and Kanzaki disease. To better understand the molecular defects in the diseases, we determined the crystal structure of human α-NAGAL after expressing wild-type and glycosylation-deficient glycoproteins in recombinant insect cell expression systems. We measured the enzymatic parameters of our purified wild-type and mutant enzymes, establishing their enzymatic equivalence. To investigate the binding specificity and catalytic mechanism of the human α-NAGAL enzyme, we determined three crystallographic complexes with different catalytic products bound in the active site of the enzyme. To better understand how individual defects in the α-NAGAL glycoprotein lead to Schindler disease, we analyzed the effect of disease-causing mutations on the three-dimensional structure.

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