Cryo-EM structures of human GMPPA–GMPPB complex reveal how cells maintain GDP-mannose homeostasis

GDP-mannose (GDP-Man) is a key metabolite essential for protein glycosylation and glycophosphatidylinositol anchor synthesis, and aberrant cellular GDP-Man levels have been associated with multiple human diseases. How cells maintain homeostasis of GDP-Man is unknown. Here, we report the cryo-EM stru...

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Veröffentlicht in:Nature structural & molecular biology 2021-05, Vol.28 (5), p.1-12
Hauptverfasser: Zheng, Lvqin, Liu, Zhe, Wang, Yan, Yang, Fan, Wang, Jinrui, Huang, Wenjie, Qin, Jiao, Tian, Min, Cai, Xiaotang, Liu, Xiaohui, Mo, Xianming, Gao, Ning, Jia, Da
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Sprache:eng
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Zusammenfassung:GDP-mannose (GDP-Man) is a key metabolite essential for protein glycosylation and glycophosphatidylinositol anchor synthesis, and aberrant cellular GDP-Man levels have been associated with multiple human diseases. How cells maintain homeostasis of GDP-Man is unknown. Here, we report the cryo-EM structures of human GMPPA–GMPPB complex, the protein machinery responsible for GDP-Man synthesis, in complex with GDP-Man or GTP. Unexpectedly, we find that the catalytically inactive subunit GMPPA displays a much higher affinity to GDP-Man than the active subunit GMPPB and, subsequently, inhibits the catalytic activity of GMPPB through a unique C-terminal loop of GMPPA. Importantly, disruption of the interactions between GMPPA and GMPPB or the binding of GDP-Man to GMPPA in zebrafish leads to abnormal brain development and muscle abnormality, analogous to phenotypes observed in individuals carrying GMPPA or GMPPB mutations. We conclude that GMPPA acts as a cellular sensor to maintain mannose homeostasis through allosterically regulating GMPPB. Structural elucidation and functional analysis of the human GMPPA–GMPPB complex reveals how GMPPA acts as a ‘sensor’ of GDP-mannose to allosterically regulate GMPPB activity.
ISSN:1545-9993
1545-9985
DOI:10.1038/s41594-021-00591-9