7D74

Cryo-EM structure of GMPPA/GMPPB complex bound to GTP (state II)

Summary for 7D74

• Entry DOI: 10.2210/pdb7d74/pdb
• EMDB information: 30601
• Descriptor: Mannose-1-phosphate guanyltransferase alpha, Mannose-1-phosphate guanyltransferase beta, GUANOSINE-5'-TRIPHOSPHATE (3 entities in total)
• Functional Keywords: gmppa, gmppb, gdp-mannose homeostasis, cell cycle, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 510672.53

Authors

Zheng, L.,Liu, Z.,Wang, Y.,Yang, F.,Wang, J.,Qing, J.,cai, X.,Mo, X.,Gao, N.,Jia, D. (deposition date: 2020-10-02, release date: 2021-05-19, Last modification date: 2021-12-01)

Primary 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.
Cryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis.
Nat.Struct.Mol.Biol., 28:1-12, 2021

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 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.

PubMed: 33986552
DOI: 10.1038/s41594-021-00591-9

Experimental method

ELECTRON MICROSCOPY (3.1 Å)