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Cited by 3Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusProteoglycans and glycosaminoglycans research

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Structure of the human heparan-α-glucosaminide N-acetyltransferase (HGSNAT)

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Navratna, Vikas, Kumar, Arvind, Rana, Jaimin K, Mosalaganti, Shyamal·2024·eLife
DOI 10.7554/elife.93510.3

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Abstract

Degradation of heparan sulfate (HS), a glycosaminoglycan (GAG) comprised of repeating units of N -acetylglucosamine and glucuronic acid, begins in the cytosol and is completed in the lysosomes. Acetylation of the terminal non-reducing amino group of α-D-glucosamine of HS is essential for its complete breakdown into monosaccharides and free sulfate. Heparan-α-glucosaminide N -acetyltransferase (HGSNAT), a resident of the lysosomal membrane, catalyzes this essential acetylation reaction by accepting and transferring the acetyl group from cytosolic acetyl-CoA to terminal α-D-glucosamine of HS in the lysosomal lumen. Mutation-induced dysfunction in HGSNAT causes abnormal accumulation of HS within the lysosomes and leads to an autosomal recessive neurodegenerative lysosomal storage disorder called mucopolysaccharidosis IIIC (MPS IIIC). There are no approved drugs or treatment strategies to cure or manage the symptoms of, MPS IIIC. Here, we use cryo-electron microscopy (cryo-EM) to determine a high-resolution structure of the HGSNAT-acetyl-CoA complex, the first step in the HGSNAT-catalyzed acetyltransferase reaction. In addition, we map the known MPS IIIC mutations onto the structure and elucidate the molecular basis for mutation-induced HGSNAT dysfunction.

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Metadata

Authors
Navratna, V., Kumar, A., Rana, J. K., & Mosalaganti, S.
Affiliations
  • University of Michigan (US)
  • Thermo Fisher Scientific (United States) (US)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-08-28
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.93510.3
OpenAlex
W4401947835
Cited by
3
References
1
Citations by year
2026: 2 · 2025: 1
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
Locations
eLife (publishedVersion, cc-by)
Funders
  • University of Michigan (Startup funding)
  • National Institutes of Health (1DP2GM150019-01)
Topics
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
HGSNAT, heparan sulfate degradation, lysosomal storage disease, acetyl-CoA, enzyme structure, glycosaminoglycan catabolism

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