8VLU

Cryo-EM structure of human HGSNAT bound with CoA

Summary for 8VLU

• Entry DOI: 10.2210/pdb8vlu/pdb
• EMDB information: 43344
• Descriptor: Heparan-alpha-glucosaminide N-acetyltransferase, 2-acetamido-2-deoxy-beta-D-glucopyranose, COENZYME A (3 entities in total)
• Functional Keywords: membrane protein, lysosome, transmembrane acetyltransferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 149813.60

Authors

Li, F.,Zhao, B. (deposition date: 2024-01-12, release date: 2024-06-26, Last modification date: 2024-11-13)

Primary citation

Zhao, B.,Cao, Z.,Zheng, Y.,Nguyen, P.,Bowen, A.,Edwards, R.H.,Stroud, R.M.,Zhou, Y.,Van Lookeren Campagne, M.,Li, F.
Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome.
Nat Commun, 15:5388-5388, 2024

PubMed Abstract: Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.

PubMed: 38918376
DOI: 10.1038/s41467-024-49614-1

Experimental method

ELECTRON MICROSCOPY (3.12 Å)