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| Title | Structure of the human GlcNAc-1-phosphotransferase αβ subunits reveals regulatory mechanism for lysosomal enzyme glycan phosphorylation. |
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| Journal, issue, pages | Nat Struct Mol Biol, Vol. 29, Issue 4, Page 348-356, Year 2022 |
| Publish date | Mar 24, 2022 |
 Authors | Hua Li / Wang-Sik Lee / Xiang Feng / Lin Bai / Benjamin C Jennings / Lin Liu / Balraj Doray / William M Canfield / Stuart Kornfeld / Huilin Li /   |
| PubMed Abstract | Vertebrates use the mannose 6-phosphate (M6P)-recognition system to deliver lysosomal hydrolases to lysosomes. Key to this pathway is N-acetylglucosamine (GlcNAc)-1-phosphotransferase (PTase) that ...Vertebrates use the mannose 6-phosphate (M6P)-recognition system to deliver lysosomal hydrolases to lysosomes. Key to this pathway is N-acetylglucosamine (GlcNAc)-1-phosphotransferase (PTase) that selectively adds GlcNAc-phosphate (P) to mannose residues of hydrolases. Human PTase is an αβγ heterohexamer with a catalytic core and several peripheral domains that recognize and bind substrates. Here we report a cryo-EM structure of the catalytic core of human PTase and the identification of a hockey stick-like motif that controls activation of the enzyme. Movement of this motif out of the catalytic pocket is associated with a rearrangement of part of the peripheral domains that unblocks hydrolase glycan access to the catalytic site, thereby activating PTase. We propose that PTase fluctuates between inactive and active states in solution, and selective substrate binding of a lysosomal hydrolase through its protein-binding determinant to PTase locks the enzyme in the active state to permit glycan phosphorylation. This mechanism would help ensure that only N-linked glycans of lysosomal enzymes are phosphorylated. |
 External links | Nat Struct Mol Biol / PubMed:35332324 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.1 - 3.3 Å |
| Structure data | EMDB-24784: Cryo-EM map of human GlcNAc-1-phosphotransferase A2B2 subcomplex EMDB-24785, PDB-7s06: |
| Chemicals |  ChemComp-NAG:  ChemComp-CA: |
| Source |
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 Keywords |  TRANSFERASE / GlcNAc-1-phosphotransferase / lysosomal hydrolases / mannose 6-phosphate trafficking pathway |
