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-Structure paper
Title | Cryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 28, Issue 5, Page 1-12, Year 2021 |
Publish date | May 13, 2021 |
![]() | Lvqin Zheng / Zhe Liu / Yan Wang / Fan Yang / Jinrui Wang / Wenjie Huang / Jiao Qin / Min Tian / Xiaotang Cai / Xiaohui Liu / Xianming Mo / Ning Gao / Da Jia / ![]() |
PubMed Abstract | 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 ...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. |
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Methods | EM (single particle) |
Resolution | 3.0 - 3.4 Å |
Structure data | EMDB-30599, PDB-7d72: EMDB-30600, PDB-7d73: EMDB-30601, PDB-7d74: |
Chemicals | ![]() ChemComp-GDD: ![]() ChemComp-MG: ![]() ChemComp-HOH: ![]() ChemComp-GTP: |
Source |
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![]() | TRANSFERASE / GMPPA / GMPPB / gdp-mannose homeostasis / CELL CYCLE |