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TitleCryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis.
Journal, issue, pagesNat Struct Mol Biol, Vol. 28, Issue 5, Page 1-12, Year 2021
Publish dateMay 13, 2021
AuthorsLvqin 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 AbstractGDP-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.
External linksNat Struct Mol Biol / PubMed:33986552
MethodsEM (single particle)
Resolution3.0 - 3.4 Å
Structure data

30599

7d72

EMDB-30599, PDB-7d72:
Cryo-EM structures of human GMPPA/GMPPB complex bound to GDP-Mannose
Method: EM (single particle) / Resolution: 3.4 Å

30600

7d73

EMDB-30600, PDB-7d73:
Cryo-EM structure of GMPPA/GMPPB complex bound to GTP (State I)
Method: EM (single particle) / Resolution: 3.0 Å

30601

7d74

EMDB-30601, PDB-7d74:
Cryo-EM structure of GMPPA/GMPPB complex bound to GTP (state II)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-GDD:
GUANOSINE-5'-DIPHOSPHATE-ALPHA-D-MANNOSE / Guanosine diphosphate mannose

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / GMPPA / GMPPB / gdp-mannose homeostasis / CELL CYCLE

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