7YEH

Cryo-EM structure of human OGT-OGA complex

Summary for 7YEH

• Entry DOI: 10.2210/pdb7yeh/pdb
• EMDB information: 33773
• Descriptor: UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110 kDa subunit, Protein O-GlcNAcase, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: o-glcnac transferase, o-glcnacase, complex, mutual inhibition, transferase, transferase-hydrolase complex, transferase/hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 442574.01

Authors

Lu, P.,Liu, Y.,Yu, H.,Gao, H. (deposition date: 2022-07-05, release date: 2023-07-12, Last modification date: 2024-01-24)

Primary citation

Lu, P.,Liu, Y.,He, M.,Cao, T.,Yang, M.,Qi, S.,Yu, H.,Gao, H.
Cryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex.
Nat Commun, 14:6952-6952, 2023

PubMed Abstract: O-GlcNAcylation is a conserved post-translational modification that attaches N-acetyl glucosamine (GlcNAc) to myriad cellular proteins. In response to nutritional and hormonal signals, O-GlcNAcylation regulates diverse cellular processes by modulating the stability, structure, and function of target proteins. Dysregulation of O-GlcNAcylation has been implicated in the pathogenesis of cancer, diabetes, and neurodegeneration. A single pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), catalyzes the addition and removal of O-GlcNAc on over 3,000 proteins in the human proteome. However, how OGT selects its native substrates and maintains the homeostatic control of O-GlcNAcylation of so many substrates against OGA is not fully understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of human OGT and the OGT-OGA complex. Our studies reveal that OGT forms a functionally important scissor-shaped dimer. Within the OGT-OGA complex structure, a long flexible OGA segment occupies the extended substrate-binding groove of OGT and positions a serine for O-GlcNAcylation, thus preventing OGT from modifying other substrates. Conversely, OGT disrupts the functional dimerization of OGA and occludes its active site, resulting in the blocking of access by other substrates. This mutual inhibition between OGT and OGA may limit the futile O-GlcNAcylation cycles and help to maintain O-GlcNAc homeostasis.

PubMed: 37907462
DOI: 10.1038/s41467-023-42427-8

Experimental method

ELECTRON MICROSCOPY (3.92 Å)