7S05

Cryo-EM structure of human GlcNAc-1-phosphotransferase A2B2 subcomplex

Summary for 7S05

• Entry DOI: 10.2210/pdb7s05/pdb
• EMDB information: 24784
• Descriptor: N-acetylglucosamine-1-phosphotransferase subunits alpha/beta, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: glcnac-1-phosphotransferase, lysosomal hydrolases, mannose 6-phosphate trafficking pathway, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 272680.01

Authors

Li, H.,Li, H. (deposition date: 2021-08-30, release date: 2022-03-30, Last modification date: 2024-10-16)

Primary citation

Li, H.,Lee, W.S.,Feng, X.,Bai, L.,Jennings, B.C.,Liu, L.,Doray, B.,Canfield, W.M.,Kornfeld, S.,Li, H.
Structure of the human GlcNAc-1-phosphotransferase alpha beta subunits reveals regulatory mechanism for lysosomal enzyme glycan phosphorylation.
Nat.Struct.Mol.Biol., 29:348-356, 2022

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 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.

PubMed: 35332324
DOI: 10.1038/s41594-022-00748-0

Experimental method

ELECTRON MICROSCOPY (3.1 Å)