| Structural highlights
8w4a is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.69Å |
| Ligands: | ACO, C14, CLR, D10, D12, HP6, NAG, OCT, R16, UV6 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
HGNAT_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.
Function
HGNAT_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]
Publication Abstract from PubMed
Lysosomal transmembrane acetylation of heparan sulfates (HS) is catalyzed by HS acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT), whose dysfunction leads to lysosomal storage diseases. The mechanism by which HGSNAT, the sole non-hydrolase enzyme in HS degradation, brings cytosolic acetyl-coenzyme A (Ac-CoA) and lysosomal HS together for N-acyltransferase reactions remains unclear. Here, we present cryogenic-electron microscopy structures of HGSNAT alone, complexed with Ac-CoA and with acetylated products. These structures explain that Ac-CoA binding from the cytosolic side causes dimeric HGSNAT to form a transmembrane tunnel. Within this tunnel, catalytic histidine and asparagine approach the lumen and instigate the transfer of the acetyl group from Ac-CoA to the glucosamine group of HS. Our study unveils a transmembrane acetylation mechanism that may help advance therapeutic strategies targeting lysosomal storage diseases.
Structure and mechanism of lysosome transmembrane acetylation by HGSNAT.,Xu R, Ning Y, Ren F, Gu C, Zhu Z, Pan X, Pshezhetsky AV, Ge J, Yu J Nat Struct Mol Biol. 2024 Oct;31(10):1502-1508. doi: 10.1038/s41594-024-01315-5. , Epub 2024 May 20. PMID:38769387[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fan X, Zhang H, Zhang S, Bagshaw RD, Tropak MB, Callahan JW, Mahuran DJ. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C). Am J Hum Genet. 2006 Oct;79(4):738-44. PMID:16960811 doi:10.1086/508068
- ↑ Hrebícek M, Mrázová L, Seyrantepe V, Durand S, Roslin NM, Nosková L, Hartmannová H, Ivánek R, Cízkova A, Poupetová H, Sikora J, Urinovská J, Stranecký V, Zeman J, Lepage P, Roquis D, Verner A, Ausseil J, Beesley CE, Maire I, Poorthuis BJ, van de Kamp J, van Diggelen OP, Wevers RA, Hudson TJ, Fujiwara TM, Majewski J, Morgan K, Kmoch S, Pshezhetsky AV. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Am J Hum Genet. 2006 Nov;79(5):807-19. PMID:17033958 doi:10.1086/508294
- ↑ Feldhammer M, Durand S, Pshezhetsky AV. Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C. PLoS One. 2009 Oct 13;4(10):e7434. PMID:19823584 doi:10.1371/journal.pone.0007434
- ↑ Durand S, Feldhammer M, Bonneil E, Thibault P, Pshezhetsky AV. Analysis of the biogenesis of heparan sulfate acetyl-CoA:alpha-glucosaminide N-acetyltransferase provides insights into the mechanism underlying its complete deficiency in mucopolysaccharidosis IIIC. J Biol Chem. 2010 Oct 8;285(41):31233-42. PMID:20650889 doi:10.1074/jbc.M110.141150
- ↑ Xu R, Ning Y, Ren F, Gu C, Zhu Z, Pan X, Pshezhetsky AV, Ge J, Yu J. Structure and mechanism of lysosome transmembrane acetylation by HGSNAT. Nat Struct Mol Biol. 2024 Oct;31(10):1502-1508. PMID:38769387 doi:10.1038/s41594-024-01315-5
|
