EMD-37264
membrane proteins
EMD-37264
Single-particle2.69 Å
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Map released: 23/10/2024
Last modified: 13/11/2024
Sample Organism:
Homo sapiens
Sample: HGSNAT
Fitted models: 8w4a (Avg. Q-score: 0.619)
Deposition Authors: Yu J
,
Ge JP,
Xu RS
Sample: HGSNAT
Fitted models: 8w4a (Avg. Q-score: 0.619)
Deposition Authors: Yu J
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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
(2024) Nat Struct Mol Biol , 31 , 1502 - 1508
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(2024) Nat Struct Mol Biol , 31 , 1502 - 1508
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.
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.