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  Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA.

Sidhu, N. S., Schreiber, K., Pröpper, K., Becker, S., Usón, I., Sheldrick, G. M., et al. (2014). Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. Acta Crystallographica D, 70(5), 1321-1335. doi:10.1107/S1399004714002739.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0019-BC6C-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CCDC-B
Genre: Journal Article

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 Creators:
Sidhu, N. S., Author
Schreiber, K., Author
Pröpper, K., Author
Becker, S.1, Author              
Usón, I., Author
Sheldrick, G. M., Author
Gärtner, J., Author
Krätzner, R., Author
Steinfeld, R., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: sulfamidase; mucopolysaccharidosis IIIA
 Abstract: Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), a fatal childhood-onset neurodegenerative disease with mild facial, visceral and skeletal abnormalities, is caused by an inherited deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH; sulfamidase). More than 100 mutations in the SGSH gene have been found to reduce or eliminate its enzymatic activity. However, the molecular understanding of the effect of these mutations has been confined by a lack of structural data for this enzyme. Here, the crystal structure of glycosylated SGSH is presented at 2 A resolution. Despite the low sequence identity between this unique N-sulfatase and the group of O-sulfatases, they share a similar overall fold and active-site architecture, including a catalytic formylglycine, a divalent metal-binding site and a sulfate-binding site. However, a highly conserved lysine in O-sulfatases is replaced in SGSH by an arginine (Arg282) that is positioned to bind the N-linked sulfate substrate. The structure also provides insight into the diverse effects of pathogenic mutations on SGSH function in mucopolysaccharidosis type IIIA and convincing evidence for the molecular consequences of many missense mutations. Further, the molecular characterization of SGSH mutations will lay the groundwork for the development of structure-based drug design for this devastating neurodegenerative disorder.

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Language(s): eng - English
 Dates: 2014-05-082014-05
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1107/S1399004714002739
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Title: Acta Crystallographica D
Source Genre: Journal
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Pages: - Volume / Issue: 70 (5) Sequence Number: - Start / End Page: 1321 - 1335 Identifier: -