
The high-resolution cryo-EM structure of the lysosomal membrane protein HGSNAT in complex with acetyl-CoA provides critical insights into the molecular basis of its N-acetyltransferase activity and the impact of mutations that cause the rare lysosomal storage disorder mucopolysaccharidosis IIIC.


coremsg

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 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.

### Competing Interest Statement

The authors have declared no competing interest.

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

high-resolution-structure-of-the-lysosomal-heparan-α-glucosaminide-n-acetyltransferase-hgsnat-reveals-insights-into-mucopolysaccharidosis-iiic


High-Resolution Structure of the Lysosomal Heparan-α-Glucosaminide N-Acetyltransferase (HGSNAT) Reveals Insights into Mucopolysaccharidosis IIIC
