PUBLICATION
Cryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis
- Authors
- Zheng, L., Liu, Z., Wang, Y., Yang, F., Wang, J., Huang, W., Qin, J., Tian, M., Cai, X., Liu, X., Mo, X., Gao, N., Jia, D.
- ID
- ZDB-PUB-210515-7
- Date
- 2021
- Source
- Nature structural & molecular biology 28: 1-12 (Journal)
- Registered Authors
- Mo, Xianming
- Keywords
- none
- MeSH Terms
-
- Animals
- Cryoelectron Microscopy
- Guanosine Diphosphate Mannose/metabolism*
- HEK293 Cells
- Humans
- Nucleotidyltransferases*/chemistry
- Nucleotidyltransferases*/metabolism
- Protein Binding
- Protein Domains
- Zebrafish
- PubMed
- 33986552 Full text @ Nat. Struct. Mol. Biol.
Citation
Zheng, L., Liu, Z., Wang, Y., Yang, F., Wang, J., Huang, W., Qin, J., Tian, M., Cai, X., Liu, X., Mo, X., Gao, N., Jia, D. (2021) Cryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis. Nature structural & molecular biology. 28:1-12.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping