7d74

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

Structural highlights

7d74 is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.1Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GMPPA_HUMAN Triple A syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

GMPPA_HUMAN Regulatory subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex; reduces the catalytic activity of GMPPB when part of the complex (PubMed:24035193, PubMed:33986552). Mediates allosteric feedback inhibition of GMPPB catalytic activity upon binding GDP-alpha-D-mannose (PubMed:24035193, PubMed:33986552). Together with GMPPB regulates GDP-alpha-D-mannose levels (PubMed:33986552).^[1] ^[2]

Publication Abstract from PubMed

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.

Cryo-EM structures of human GMPPA-GMPPB complex reveal how cells maintain GDP-mannose homeostasis.,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 Nat Struct Mol Biol. 2021 May;28(5):1-12. doi: 10.1038/s41594-021-00591-9. Epub , 2021 May 13. PMID:33986552^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Koehler K, Malik M, Mahmood S, Gießelmann S, Beetz C, Hennings JC, Huebner AK, Grahn A, Reunert J, Nürnberg G, Thiele H, Altmüller J, Nürnberg P, Mumtaz R, Babovic-Vuksanovic D, Basel-Vanagaite L, Borck G, Brämswig J, Mühlenberg R, Sarda P, Sikiric A, Anyane-Yeboa K, Zeharia A, Ahmad A, Coubes C, Wada Y, Marquardt T, Vanderschaeghe D, Van Schaftingen E, Kurth I, Huebner A, Hübner CA. Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. Am J Hum Genet. 2013 Oct 3;93(4):727-34. PMID:24035193 doi:10.1016/j.ajhg.2013.08.002
↑ 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. 2021 May;28(5):1-12. PMID:33986552 doi:10.1038/s41594-021-00591-9
↑ 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. 2021 May;28(5):1-12. PMID:33986552 doi:10.1038/s41594-021-00591-9

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Koehler K, Malik M, Mahmood S, Gießelmann S, Beetz C, Hennings JC, Huebner AK, Grahn A, Reunert J, Nürnberg G, Thiele H, Altmüller J, Nürnberg P, Mumtaz R, Babovic-Vuksanovic D, Basel-Vanagaite L, Borck G, Brämswig J, Mühlenberg R, Sarda P, Sikiric A, Anyane-Yeboa K, Zeharia A, Ahmad A, Coubes C, Wada Y, Marquardt T, Vanderschaeghe D, Van Schaftingen E, Kurth I, Huebner A, Hübner CA. Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction. Am J Hum Genet. 2013 Oct 3;93(4):727-34. PMID:24035193 doi:10.1016/j.ajhg.2013.08.002

[2] 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. 2021 May;28(5):1-12. PMID:33986552 doi:10.1038/s41594-021-00591-9

[3] 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. 2021 May;28(5):1-12. PMID:33986552 doi:10.1038/s41594-021-00591-9

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