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PXD020451

PXD020451 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleProtein kinase A controls the hexosamine pathway by tuning feedback inhibition of GFAT-1
DescriptionThe hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5’-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for all glycosylation processes in mammals. It modulates the ER stress response, is implicated in cancer and diabetes, and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT 1) is the first and rate-limiting HP enzyme. GFAT 1 activity is modulated through UDP-GlcNAc feedback inhibition and by kinase signaling, including Ser205 phosphorylation by protein kinase A (PKA). The consequence and molecular mechanism of GFAT 1 PKA phosphorylation, however, remains poorly understood. Here, we identify the GFAT 1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans, leading to ER stress resistance. In human GFAT-1, the R203H substitution interfered with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Of note, Ser205 phosphorylation had two discernible effects: It lowered baseline GFAT 1 activity while abolishing UDP-GlcNAc feedback inhibition. Thus, GFAT-1 phosphorylation by PKA uncoupled the feedback loop of the HP and depending on UDP-GlcNAc availability, phosphorylation by PKA lowers or enhances GFAT 1 activity in vivo. Mechanistically, our data indicate that the relative positioning of the two GFAT 1 domains might be affected by phosphorylation and we propose a model how Ser205 phosphorylation modulates the activity and feedback inhibition of GFAT 1.
HostingRepositoryPRIDE
AnnounceDate2020-07-23
AnnouncementXMLSubmission_2021-04-22_22:49:06.064.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterIlian Atanassov
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-07-20 05:25:52ID requested
12020-07-22 23:25:21announced
22021-04-22 22:49:06announced2021-04-23: Updated publication reference for PubMed record(s): 33846315.
Publication List
Ruegenberg S, Mayr FAMC, Atanassov I, Baumann U, Denzel MS, Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1. Nat Commun, 12(1):2176(2021) [pubmed]
Keyword List
submitter keyword: Human, PKA, phosphorylation
Contact List
Martin S. Denzel
contact affiliationMax Planck Institute for Biology of Ageing D-50931 Cologne, Germany CECAD - Cluster of Excellence University of Cologne D-50931 Cologne, Germany Center for Molecular Medicine Cologne (CMMC) University of Cologne D-50931 Cologne, Germany
contact emailmartin.denzel@age.mpg.de
lab head
Ilian Atanassov
contact affiliationMax Planck Institute for Biology of Aging
contact emailIlian.Atanassov@age.mpg.de
dataset submitter
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