Insights into Hunter syndrome from the structure of iduronate-2-sulfatase

Mykhaylo Demydchuk, Chris H. Hill, Aiwu Zhou, Gábor Bunkóczi, Penelope E. Stein, Denis Marchesan, Janet E. Deane and Randy J. Read ()
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Mykhaylo Demydchuk: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge Biomedical Campus
Chris H. Hill: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge Biomedical Campus
Aiwu Zhou: Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Shanghai Jiaotong University School of Medicine
Gábor Bunkóczi: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge Biomedical Campus
Penelope E. Stein: University of Cambridge, Cambridge Biomedical Campus
Denis Marchesan: University of Cambridge, Cambridge Biomedical Campus
Janet E. Deane: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge Biomedical Campus
Randy J. Read: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge Biomedical Campus

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15786

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