Insights into Mucopolysaccharidosis I from the structure and action of α-L-Iduronidase
| Autor: | Haiying Bie, Ethan D. Goddard-Borger, Jiang Yin, Allison R. Kermode, Stephen G. Withers, Xu He, Michael N.G. James |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Protein Conformation Mucopolysaccharidosis I Mutant medicine.disease_cause Crystallography X-Ray Article 03 medical and health sciences Mucopolysaccharidosis type I Iduronidase 0302 clinical medicine Protein structure TIM barrel medicine Humans Molecular Biology 030304 developmental biology 0303 health sciences Mutation biology Chemistry Active site Cell Biology Biochemistry biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Mucopolysaccharidosis type I (MPS I), caused by mutations in the gene encoding α-L-iduronidase (IDUA), is one of approximately 70 genetic disorders collectively known as the lysosomal storage diseases. To gain insight into the basis for MPS I, we have crystallized human IDUA produced in an Arabidopsis thaliana cgl mutant. IDUA consists of a TIM barrel domain containing the catalytic site, a β-sandwich domain and a fibronectin-like domain. Structures of IDUA bound to induronate analogues illustrate the Michaelis complex and reveal a 2,5B conformation in the glycosyl-enzyme intermediate, that suggest a retaining double displacement reaction employing the nucleophilic Glu299 and the general acid/base Glu182. Surprisingly, the N-glycan attached to Asn372 interacts with iduronate analogues in the active site and is required for enzymatic activity. Finally, these IDUA structures and biochemical analysis of the disease-relevant Pro533Arg mutation have enabled us to correlate the effects of mutations in IDUA to clinical phenotypes. |
| Databáze: | OpenAIRE |
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