6r4h: Difference between revisions
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<StructureSection load='6r4h' size='340' side='right'caption='[[6r4h]], [[Resolution|resolution]] 2.24Å' scene=''> | <StructureSection load='6r4h' size='340' side='right'caption='[[6r4h]], [[Resolution|resolution]] 2.24Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6r4h]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6r4h]] is a 2 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=6R4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R4H FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.244Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G6Q:GLUCOSE-6-PHOSPHATE'>G6Q</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=6r4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r4h OCA], [https://pdbe.org/6r4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r4h RCSB], [https://www.ebi.ac.uk/pdbsum/6r4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r4h ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/GFPT1_HUMAN GFPT1_HUMAN] Defects in GFPT1 are the cause of myasthenia, congenital, with tubular aggregates, type 1 (CMSTA1) [MIM:[https://omim.org/entry/610542 610542]. A congenital myasthenic syndrome characterized by onset of proximal muscle weakness in the first decade. Individuals with this condition have a recognizable pattern of weakness of shoulder and pelvic girdle muscles, and sparing of ocular or facial muscles. EMG classically shows a decremental response to repeated nerve stimulation, a sign of neuromuscular junction dysfunction. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors.<ref>PMID:21310273</ref> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/GFPT1_HUMAN GFPT1_HUMAN] Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 21: | ||
</div> | </div> | ||
<div class="pdbe-citations 6r4h" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6r4h" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Aminotransferase 3D structures|Aminotransferase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Allmeroth | [[Category: Allmeroth K]] | ||
[[Category: Baumann | [[Category: Baumann U]] | ||
[[Category: Denzel | [[Category: Denzel MS]] | ||
[[Category: Horn | [[Category: Horn M]] | ||
[[Category: Pichlo | [[Category: Pichlo C]] | ||
[[Category: Ruegenberg | [[Category: Ruegenberg S]] | ||
Latest revision as of 15:14, 24 January 2024
Crystal structure of human GFAT-1 G451ECrystal structure of human GFAT-1 G451E
Structural highlights
DiseaseGFPT1_HUMAN Defects in GFPT1 are the cause of myasthenia, congenital, with tubular aggregates, type 1 (CMSTA1) [MIM:610542. A congenital myasthenic syndrome characterized by onset of proximal muscle weakness in the first decade. Individuals with this condition have a recognizable pattern of weakness of shoulder and pelvic girdle muscles, and sparing of ocular or facial muscles. EMG classically shows a decremental response to repeated nerve stimulation, a sign of neuromuscular junction dysfunction. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors.[1] FunctionGFPT1_HUMAN Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Publication Abstract from PubMedGlutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies. Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis.,Ruegenberg S, Horn M, Pichlo C, Allmeroth K, Baumann U, Denzel MS Nat Commun. 2020 Feb 4;11(1):687. doi: 10.1038/s41467-020-14524-5. PMID:32019926[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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