8tu9
Cryo-EM structure of HGSNAT-acetyl-CoA complex at pH 7.5
Structural highlights
DiseaseHGNAT_HUMAN Retinitis pigmentosa;Sanfilippo syndrome type C. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionHGNAT_HUMAN Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.[1] [2] [3] [4] GFP_AEQVI Energy-transfer acceptor. Its role is to transduce the blue chemiluminescence of the protein aequorin into green fluorescent light by energy transfer. Fluoresces in vivo upon receiving energy from the Ca(2+)-activated photoprotein aequorin. Publication Abstract from PubMedDegradation 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 alpha-D-glucosamine of HS is essential for its complete breakdown into monosaccharides and free sulfate. Heparan-alpha-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 alpha-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. Structure of the human heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).,Navratna V, Kumar A, Rana JK, Mosalaganti S Elife. 2024 Aug 28;13:RP93510. doi: 10.7554/eLife.93510. PMID:39196614[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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