Structure and mechanism of lysosome transmembrane acetylation by HGSNAT

Ruisheng Xu; Yingjie Ning; Fandong Ren; Chenxia Gu; Zhengjiang Zhu; Xuefang Pan; Alexey V Pshezhetsky; Jingpeng Ge; Jie Yu

doi:10.1038/s41594-024-01315-5

Structure and mechanism of lysosome transmembrane acetylation by HGSNAT

Nat Struct Mol Biol. 2024 May 20. doi: 10.1038/s41594-024-01315-5. Online ahead of print.

Authors

Ruisheng Xu^#^{1

2}, Yingjie Ning^#³, Fandong Ren¹, Chenxia Gu³, Zhengjiang Zhu¹, Xuefang Pan⁴, Alexey V Pshezhetsky^{5

6}, Jingpeng Ge⁷, Jie Yu^{8

9}

Affiliations

¹ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁴ Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, Quebec, Canada.
⁵ Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, Quebec, Canada. alexei.pchejetski@umontreal.ca.
⁶ Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada. alexei.pchejetski@umontreal.ca.
⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. gejp@shanghaitech.edu.cn.
⁸ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. yujie@sioc.ac.cn.
⁹ Shanghai Key Laboratory of Aging Studies, Shanghai, China. yujie@sioc.ac.cn.

^# Contributed equally.

PMID: 38769387
DOI: 10.1038/s41594-024-01315-5

Abstract

Lysosomal transmembrane acetylation of heparan sulfates (HS) is catalyzed by HS acetyl-CoA:α-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.