7d74: Difference between revisions
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The entry | ==Cryo-EM structure of GMPPA/GMPPB complex bound to GTP (state II)== | ||
<StructureSection load='7d74' size='340' side='right'caption='[[7d74]], [[Resolution|resolution]] 3.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7d74]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D74 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D74 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7d74 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d74 OCA], [https://pdbe.org/7d74 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d74 RCSB], [https://www.ebi.ac.uk/pdbsum/7d74 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d74 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/GMPPA_HUMAN GMPPA_HUMAN] Triple A syndrome. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GMPPA_HUMAN 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).<ref>PMID:24035193</ref> <ref>PMID:33986552</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:33986552</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7d74" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gao N]] | |||
[[Category: Jia D]] | |||
[[Category: Liu Z]] | |||
[[Category: Mo X]] | |||
[[Category: Qing J]] | |||
[[Category: Wang J]] | |||
[[Category: Wang Y]] | |||
[[Category: Yang F]] | |||
[[Category: Zheng L]] | |||
[[Category: Cai X]] | |||
Latest revision as of 16:30, 6 November 2024
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
DiseaseGMPPA_HUMAN Triple A syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionGMPPA_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 PubMedGDP-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
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