PXD020451

PXD020451 is an original dataset announced via ProteomeXchange.

Title	Protein kinase A controls the hexosamine pathway by tuning feedback inhibition of GFAT-1
Description	The 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.
HostingRepository	PRIDE
AnnounceDate	2020-07-23
AnnouncementXML	Submission_2021-04-22_22:49:06.064.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ilian Atanassov
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-20 05:25:52	ID requested
1	2020-07-22 23:25:21	announced
⏵ 2	2021-04-22 22:49:06	announced	2021-04-23: Updated publication reference for PubMed record(s): 33846315.

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]

submitter keyword: Human, PKA, phosphorylation

Martin S. Denzel
contact affiliation	Max 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 email	martin.denzel@age.mpg.de
lab head
Ilian Atanassov
contact affiliation	Max Planck Institute for Biology of Aging
contact email	Ilian.Atanassov@age.mpg.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/07/PXD020451

PRIDE project URI

• PRIDE
  1. PXD020451
     1. Label: PRIDE project
     2. Name: Protein kinase A controls the hexosamine pathway by tuning feedback inhibition of GFAT-1