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Protein

Glycogen synthase kinase-3 alpha

Gene

GSK3A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation.2 Publications

Catalytic activityi

ATP + [tau protein] = ADP + [tau protein] phosphate.
ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei148ATPPROSITE-ProRule annotation1
Active sitei244Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi125 – 133ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • protein kinase A catalytic subunit binding Source: BHF-UCL
  • protein serine/threonine kinase activity Source: BHF-UCL
  • tau-protein kinase activity Source: UniProtKB

GO - Biological processi

  • cardiac left ventricle morphogenesis Source: BHF-UCL
  • cellular response to insulin stimulus Source: BHF-UCL
  • cellular response to interleukin-3 Source: UniProtKB
  • chemical synaptic transmission, postsynaptic Source: ParkinsonsUK-UCL
  • dopamine receptor signaling pathway Source: ParkinsonsUK-UCL
  • extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
  • glycogen metabolic process Source: UniProtKB-KW
  • insulin receptor signaling pathway Source: BHF-UCL
  • IRE1-mediated unfolded protein response Source: Reactome
  • negative regulation of canonical Wnt signaling pathway Source: UniProtKB
  • negative regulation of cell growth involved in cardiac muscle cell development Source: BHF-UCL
  • negative regulation of glucose import Source: BHF-UCL
  • negative regulation of glycogen (starch) synthase activity Source: UniProtKB
  • negative regulation of glycogen biosynthetic process Source: UniProtKB
  • negative regulation of glycogen synthase activity, transferring glucose-1-phosphate Source: BHF-UCL
  • negative regulation of insulin receptor signaling pathway Source: BHF-UCL
  • negative regulation of TOR signaling Source: BHF-UCL
  • negative regulation of type B pancreatic cell development Source: UniProtKB
  • negative regulation of UDP-glucose catabolic process Source: UniProtKB
  • nervous system development Source: UniProtKB-KW
  • positive regulation of adrenergic receptor signaling pathway Source: BHF-UCL
  • positive regulation of cAMP biosynthetic process Source: BHF-UCL
  • positive regulation of glycogen (starch) synthase activity Source: BHF-UCL
  • positive regulation of heart contraction Source: BHF-UCL
  • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway Source: UniProtKB
  • positive regulation of protein catabolic process Source: BHF-UCL
  • positive regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  • protein phosphorylation Source: BHF-UCL
  • regulation of mitophagy Source: ParkinsonsUK-UCL
  • regulation of systemic arterial blood pressure Source: BHF-UCL
  • Wnt signaling pathway Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Signal transduction inhibitor, Transferase

Keywords - Biological processi

Carbohydrate metabolism, Glycogen metabolism, Neurogenesis, Wnt signaling pathway

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS02806-MONOMER.
ReactomeiR-HSA-198323. AKT phosphorylates targets in the cytosol.
R-HSA-381038. XBP1(S) activates chaperone genes.
R-HSA-5674400. Constitutive Signaling by AKT1 E17K in Cancer.
SignaLinkiP49840.
SIGNORiP49840.

Names & Taxonomyi

Protein namesi
Recommended name:
Glycogen synthase kinase-3 alpha (EC:2.7.11.26)
Short name:
GSK-3 alpha
Alternative name(s):
Serine/threonine-protein kinase GSK3A (EC:2.7.11.1)
Gene namesi
Name:GSK3A
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4616. GSK3A.

Subcellular locationi

GO - Cellular componenti

  • beta-catenin destruction complex Source: UniProtKB
  • cytosol Source: BHF-UCL
  • mitochondrion Source: GOC
  • postsynapse Source: GOC
Complete GO annotation...

Pathology & Biotechi

Keywords - Diseasei

Alzheimer disease, Diabetes mellitus

Organism-specific databases

DisGeNETi2931.
OpenTargetsiENSG00000105723.
PharmGKBiPA29008.

Chemistry databases

ChEMBLiCHEMBL2850.
GuidetoPHARMACOLOGYi2029.

Polymorphism and mutation databases

BioMutaiGSK3A.
DMDMi12644292.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000859782 – 483Glycogen synthase kinase-3 alphaAdd BLAST482

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1
Modified residuei2PhosphoserineCombined sources1
Modified residuei21Phosphoserine; by PKB/AKT1By similarity1
Modified residuei72PhosphoserineCombined sources1
Modified residuei77PhosphoserineCombined sources1
Modified residuei97PhosphoserineCombined sources1
Modified residuei279PhosphotyrosineBy similarity1
Modified residuei453PhosphothreonineBy similarity1
Modified residuei466PhosphothreonineBy similarity1

Post-translational modificationi

Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279.

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP49840.
MaxQBiP49840.
PaxDbiP49840.
PeptideAtlasiP49840.
PRIDEiP49840.

PTM databases

iPTMnetiP49840.
PhosphoSitePlusiP49840.

Expressioni

Gene expression databases

BgeeiENSG00000105723.
CleanExiHS_GSK3A.
ExpressionAtlasiP49840. baseline and differential.
GenevisibleiP49840. HS.

Organism-specific databases

HPAiCAB004422.
HPA028423.

Interactioni

Subunit structurei

Monomer. Interacts with ARRB2 (By similarity). Interacts with AXIN1 and CTNNB1/beta-catenin. Interacts with CTNND2 (PubMed:19706605).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AXIN1O151693EBI-1044067,EBI-710484
DEAF1O753982EBI-1044067,EBI-718185
HSP90AB1P082382EBI-1044067,EBI-352572
LRP6O755812EBI-1044067,EBI-910915
ZDHHC17Q8IUH53EBI-1044067,EBI-524753

GO - Molecular functioni

  • protein kinase A catalytic subunit binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi109186. 65 interactors.
IntActiP49840. 42 interactors.
MINTiMINT-1688290.
STRINGi9606.ENSP00000222330.

Chemistry databases

BindingDBiP49840.

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2DFMmodel-A98-449[»]
ProteinModelPortaliP49840.
SMRiP49840.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini119 – 403Protein kinasePROSITE-ProRule annotationAdd BLAST285

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi3 – 83Gly-richAdd BLAST81

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0658. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00520000055635.
HOGENOMiHOG000233017.
HOVERGENiHBG014652.
InParanoidiP49840.
KOiK08822.
OMAiFDELRCP.
OrthoDBiEOG091G099S.
PhylomeDBiP49840.
TreeFamiTF101104.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P49840-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK
60 70 80 90 100
ASVGAMGGGV GASSSGGGPG GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV
110 120 130 140 150
TTVVATLGQG PERSQEVAYT DIKVIGNGSF GVVYQARLAE TRELVAIKKV
160 170 180 190 200
LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY SSGEKKDELY LNLVLEYVPE
210 220 230 240 250
TVYRVARHFT KAKLTIPILY VKVYMYQLFR SLAYIHSQGV CHRDIKPQNL
260 270 280 290 300
LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS
310 320 330 340 350
IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN
360 370 380 390 400
YTEFKFPQIK AHPWTKVFKS RTPPEAIALC SSLLEYTPSS RLSPLEACAH
410 420 430 440 450
SFFDELRCLG TQLPNNRPLP PLFNFSAGEL SIQPSLNAIL IPPHLRSPAG
460 470 480
TTTLTPSSQA LTETPTSSDW QSTDATPTLT NSS
Length:483
Mass (Da):50,981
Last modified:December 1, 2000 - v2
Checksum:iF18C012C03B7D786
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti449A → S in AAA62432 (Ref. 1) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_051625109Q → E.Corresponds to variant rs35978177dbSNPEnsembl.1
Natural variantiVAR_040539461L → F.1 PublicationCorresponds to variant rs35454502dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L40027 mRNA. Translation: AAA62432.1.
D63424 mRNA. Translation: BAA23608.1.
AC006486 Genomic DNA. Translation: AAD11986.1.
BC027984 mRNA. Translation: AAH27984.1.
BC051865 mRNA. Translation: AAH51865.1.
CCDSiCCDS12599.1.
RefSeqiNP_063937.2. NM_019884.2.
UniGeneiHs.466828.

Genome annotation databases

EnsembliENST00000222330; ENSP00000222330; ENSG00000105723.
ENST00000453535; ENSP00000412663; ENSG00000105723.
GeneIDi2931.
KEGGihsa:2931.
UCSCiuc002otb.2. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L40027 mRNA. Translation: AAA62432.1.
D63424 mRNA. Translation: BAA23608.1.
AC006486 Genomic DNA. Translation: AAD11986.1.
BC027984 mRNA. Translation: AAH27984.1.
BC051865 mRNA. Translation: AAH51865.1.
CCDSiCCDS12599.1.
RefSeqiNP_063937.2. NM_019884.2.
UniGeneiHs.466828.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2DFMmodel-A98-449[»]
ProteinModelPortaliP49840.
SMRiP49840.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109186. 65 interactors.
IntActiP49840. 42 interactors.
MINTiMINT-1688290.
STRINGi9606.ENSP00000222330.

Chemistry databases

BindingDBiP49840.
ChEMBLiCHEMBL2850.
GuidetoPHARMACOLOGYi2029.

PTM databases

iPTMnetiP49840.
PhosphoSitePlusiP49840.

Polymorphism and mutation databases

BioMutaiGSK3A.
DMDMi12644292.

Proteomic databases

EPDiP49840.
MaxQBiP49840.
PaxDbiP49840.
PeptideAtlasiP49840.
PRIDEiP49840.

Protocols and materials databases

DNASUi2931.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000222330; ENSP00000222330; ENSG00000105723.
ENST00000453535; ENSP00000412663; ENSG00000105723.
GeneIDi2931.
KEGGihsa:2931.
UCSCiuc002otb.2. human.

Organism-specific databases

CTDi2931.
DisGeNETi2931.
GeneCardsiGSK3A.
HGNCiHGNC:4616. GSK3A.
HPAiCAB004422.
HPA028423.
MIMi606784. gene.
neXtProtiNX_P49840.
OpenTargetsiENSG00000105723.
PharmGKBiPA29008.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0658. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00520000055635.
HOGENOMiHOG000233017.
HOVERGENiHBG014652.
InParanoidiP49840.
KOiK08822.
OMAiFDELRCP.
OrthoDBiEOG091G099S.
PhylomeDBiP49840.
TreeFamiTF101104.

Enzyme and pathway databases

BioCyciZFISH:HS02806-MONOMER.
ReactomeiR-HSA-198323. AKT phosphorylates targets in the cytosol.
R-HSA-381038. XBP1(S) activates chaperone genes.
R-HSA-5674400. Constitutive Signaling by AKT1 E17K in Cancer.
SignaLinkiP49840.
SIGNORiP49840.

Miscellaneous databases

ChiTaRSiGSK3A. human.
GeneWikiiGSK3A.
GenomeRNAii2931.
PROiP49840.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000105723.
CleanExiHS_GSK3A.
ExpressionAtlasiP49840. baseline and differential.
GenevisibleiP49840. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGSK3A_HUMAN
AccessioniPrimary (citable) accession number: P49840
Secondary accession number(s): O14959
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: December 1, 2000
Last modified: November 30, 2016
This is version 170 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

Higher expression and activity of GSK3A are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350).2 Publications

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.