9bgf | pdb_00009bgf
Structure of human GlcNAc-1-phosphotransferase complexed with the donor substrate UDP-GlcNAc
Structural highlights
DiseaseGNPTA_HUMAN Mucolipidosis type 2;Mucolipidosis type 3. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Defects in GNPTAB have been suggested to play a role in susceptibility to persistent stuttering. Stuttering is a common speech disorder characterized by repetitions, prolongations, and interruptions in the flow of speech.[1] FunctionGNPTA_HUMAN Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. M6P residues are required to bind to the M6P receptors (MPR), which mediate the vesicular transport of lysosomal enzymes to the endosomal/prelysosomal compartment.[2] [3] Publication Abstract from PubMedMutations that cause loss of function of GlcNAc-1-phosphotransferase (PTase) lead to the lysosomal storage disorder mucolipidosis II. PTase is the key enzyme of the mannose 6-phosphate (M6P) targeting system that is responsible for tagging lysosomal hydrolases with the M6P moiety for their delivery to the lysosome. We had previously generated a truncated hyperactive form of PTase termed S1S3 which was shown to notably increase the phosphorylation level of secreted lysosomal enzymes and enhance their uptake by cells. Here, we report the 3.4 A cryo-EM structure of soluble S1S3 lacking both transmembrane domains and cytosolic tails. The structure reveals a high degree of conservation of the catalytic core to full-length PTase. In this dimeric structure, the EF-hand of one protomer is observed interacting with the conserved region four of the other. In addition, we present a high-quality EM 3D map of the UDP-GlcNAc bound form of the full-length soluble protein showing the key molecular interactions between the nucleotide sugar donor and side chain amino acids of the protein. Finally, although the domain organization of S1S3 is very similar to that of the Drosophila melanogaster (fruit fly) PTase homolog, we establish that the latter does not act on lysosomal hydrolases. Structure of a truncated human GlcNAc-1-phosphotransferase variant reveals the basis for its hyperactivity.,Li H, Doray B, Jennings BC, Lee WS, Liu L, Kornfeld S, Li H J Biol Chem. 2024 Sep;300(9):107706. doi: 10.1016/j.jbc.2024.107706. Epub 2024 , Aug 22. PMID:39178950[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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