Abstract
Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. A variety of disease-causing mutations have been identified throughout the IDS gene. However, understanding the molecular basis of the disease has been impaired by the lack of structural data. Here, we present the crystal structure of human IDS with a covalently bound sulfate ion in the active site. This structure provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. Understanding the structural consequences of disease-associated mutations will facilitate the identification of patients that may benefit from specific tailored therapies.
Highlights
Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate
We report a specific activity of 36 mmol h À 1mg À 1 at room temperature (293 K)
Two mechanisms for sulfate-ester hydrolysis have been proposed based on crystal structures of human arylsulfatase A (ARSA), human arylsulfatase B (ARSB) and Pseudomonas arylsulfatase (PAS), and studies on the enzyme kinetics of active-site mutants[30]
Summary
Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. Over 500 mutations at the IDS locus (Xq28) have been identified, including complex rearrangements, insertions/deletions, splicing defects and missense/nonsense point mutations This molecular heterogeneity results in a broad spectrum of disease phenotypes, and combined with the rarity of individual mutations, the fact that most mutations are private/familial, and the lack of standardized severity reporting, genotype/phenotype correlations have been difficult to establish[5,6]. Pharmacological chaperone therapy may be a useful alternative strategy for folding mutants with residual catalytic activity, as has been demonstrated for other lysosomal storage disorders[14]
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