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

Author

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  • Ping Lu

    (Zhejiang University
    Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Yusong Liu

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Fudan University)

  • Maozhou He

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Ting Cao

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Mengquan Yang

    (Zhejiang University
    Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Shutao Qi

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Hongtao Yu

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Haishan Gao

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine)

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.

Suggested Citation

  • Ping Lu & Yusong Liu & Maozhou He & Ting Cao & Mengquan Yang & Shutao Qi & Hongtao Yu & Haishan Gao, 2023. "Cryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42427-8
    DOI: 10.1038/s41467-023-42427-8
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    References listed on IDEAS

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    1. Michael B. Lazarus & Yunsun Nam & Jiaoyang Jiang & Piotr Sliz & Suzanne Walker, 2011. "Structure of human O-GlcNAc transferase and its complex with a peptide substrate," Nature, Nature, vol. 469(7331), pages 564-567, January.
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