Cryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex

Ping Lu, Yusong Liu, Maozhou He, Ting Cao, Mengquan Yang, Shutao Qi, Hongtao Yu () and Haishan Gao ()
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Ping Lu: Zhejiang University
Yusong Liu: Westlake University
Maozhou He: Westlake University
Ting Cao: Westlake University
Mengquan Yang: Zhejiang University
Shutao Qi: Westlake University
Hongtao Yu: Westlake University
Haishan Gao: Westlake University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42427-8

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