Title : X-ray structure of human
acid-beta-glucosidase , the defective
enzyme in Gaucher disease
Abstract :
- Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (GlcCerase)
- Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms
- No clear correlation exists between the approximately 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non- neuronopathic and neuronopathic disease, respectively
- We report the X-ray structure of GlcCerase at 2.0 A resolution
- The catalytic domain consists of a (beta/alpha)( 8) TIM barrel, as expected for a member of the glucosidase hydrolase A clan
- The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention
- N370 is located on the longest alpha-helix (helix 7), which has several other mutations of residues that point into the TIM barrel
- Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain
- The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase
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