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Protein

5'-AMP-activated protein kinase catalytic subunit alpha-2

Gene

Prkaa2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization (By similarity). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (PubMed:23332761).By similarity16 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.By similarity
ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate.By similarity
ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate.By similarity

Cofactori

Mg2+By similarity

Enzyme regulationi

Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation.4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei45ATP1
Active sitei139Proton acceptorPROSITE-ProRule annotationBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi22 – 30ATPPROSITE-ProRule annotationBy similarity9

GO - Molecular functioni

  • [acetyl-CoA carboxylase] kinase activity Source: UniProtKB-EC
  • [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity Source: UniProtKB-EC
  • AMP-activated protein kinase activity Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • chromatin binding Source: UniProtKB
  • histone serine kinase activity Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • protein serine/threonine/tyrosine kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • autophagy Source: UniProtKB-KW
  • cellular response to calcium ion Source: ARUK-UCL
  • cellular response to drug Source: MGI
  • cellular response to glucose starvation Source: UniProtKB
  • cellular response to glucose stimulus Source: ARUK-UCL
  • cellular response to nutrient levels Source: UniProtKB
  • cellular response to oxidative stress Source: ARUK-UCL
  • cellular response to prostaglandin E stimulus Source: MGI
  • cholesterol biosynthetic process Source: UniProtKB-KW
  • energy homeostasis Source: UniProtKB
  • fatty acid biosynthetic process Source: UniProtKB-KW
  • fatty acid homeostasis Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • lipid biosynthetic process Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of gene expression Source: ARUK-UCL
  • negative regulation of TOR signaling Source: UniProtKB
  • negative regulation of tubulin deacetylation Source: ARUK-UCL
  • positive regulation of autophagy Source: UniProtKB
  • positive regulation of cellular protein localization Source: ARUK-UCL
  • positive regulation of glycolytic process Source: UniProtKB
  • positive regulation of peptidyl-lysine acetylation Source: ARUK-UCL
  • protein phosphorylation Source: UniProtKB
  • regulation of circadian rhythm Source: UniProtKB
  • regulation of gene expression Source: MGI
  • regulation of macroautophagy Source: UniProtKB
  • regulation of microtubule cytoskeleton organization Source: ARUK-UCL
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • response to muscle activity Source: MGI
  • response to stress Source: UniProtKB
  • rhythmic process Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW
  • Wnt signaling pathway Source: UniProtKB-KW

Keywordsi

Molecular functionChromatin regulator, Kinase, Serine/threonine-protein kinase, Transferase
Biological processAutophagy, Biological rhythms, Cholesterol biosynthesis, Cholesterol metabolism, Fatty acid biosynthesis, Fatty acid metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol biosynthesis, Sterol metabolism, Transcription, Transcription regulation, Wnt signaling pathway
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-1632852 Macroautophagy
R-MMU-163680 AMPK inhibits chREBP transcriptional activation activity
R-MMU-200425 Import of palmitoyl-CoA into the mitochondrial matrix
R-MMU-380972 Energy dependent regulation of mTOR by LKB1-AMPK
R-MMU-5628897 TP53 Regulates Metabolic Genes
R-MMU-6804756 Regulation of TP53 Activity through Phosphorylation

Names & Taxonomyi

Protein namesi
Recommended name:
5'-AMP-activated protein kinase catalytic subunit alpha-2 (EC:2.7.11.1By similarity)
Short name:
AMPK subunit alpha-2
Alternative name(s):
Acetyl-CoA carboxylase kinase (EC:2.7.11.27By similarity)
Short name:
ACACA kinase
Hydroxymethylglutaryl-CoA reductase kinase (EC:2.7.11.31By similarity)
Short name:
HMGCR kinase
Gene namesi
Name:Prkaa2Imported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1336173 Prkaa2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice develop obesity when animals are fed a high-fat diet, as a result of an enhanced lipid accumulation in pre-existing adipocytes but not in other tissues.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi45K → A: Loss of kinase activity. 1 Publication1
Mutagenesisi157D → A: Loss of kinase activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL1255154

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002629571 – 5525'-AMP-activated protein kinase catalytic subunit alpha-2Add BLAST552

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei172Phosphothreonine; by LKB1 and CaMKK23 Publications1
Modified residuei258PhosphothreonineBy similarity1
Modified residuei377PhosphoserineCombined sources1
Modified residuei491PhosphoserineBy similarity1

Post-translational modificationi

Ubiquitinated.By similarity
Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1) (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ8BRK8
PaxDbiQ8BRK8
PeptideAtlasiQ8BRK8
PRIDEiQ8BRK8

PTM databases

iPTMnetiQ8BRK8
PhosphoSitePlusiQ8BRK8

Expressioni

Gene expression databases

BgeeiENSMUSG00000028518
GenevisibleiQ8BRK8 MM

Interactioni

Subunit structurei

AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2 (By similarity).By similarity

Protein-protein interaction databases

BioGridi223817, 2 interactors
IntActiQ8BRK8, 2 interactors
STRINGi10090.ENSMUSP00000030243

Structurei

3D structure databases

ProteinModelPortaliQ8BRK8
SMRiQ8BRK8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini16 – 268Protein kinasePROSITE-ProRule annotationAdd BLAST253

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni291 – 376AISBy similarityAdd BLAST86

Domaini

The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.By similarity

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0586 Eukaryota
ENOG410XNQ0 LUCA
GeneTreeiENSGT00900000140868
HOGENOMiHOG000233016
HOVERGENiHBG050432
InParanoidiQ8BRK8
KOiK07198
OMAiRWHFGIR
OrthoDBiEOG091G03TG
TreeFamiTF314032

Family and domain databases

InterProiView protein in InterPro
IPR032270 AMPK_C
IPR028375 KA1/Ssp2_C
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF16579 AdenylateSensor, 1 hit
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF103243 SSF103243, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequencei

Sequence statusi: Complete.

Q8BRK8-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAEKQKHDGR VKIGHYVLGD TLGVGTFGKV KIGEHQLTGH KVAVKILNRQ
60 70 80 90 100
KIRSLDVVGK IKREIQNLKL FRHPHIIKLY QVISTPTDFF MVMEYVSGGE
110 120 130 140 150
LFDYICKHGR VEEVEARRLF QQILSAVDYC HRHMVVHRDL KPENVLLDAQ
160 170 180 190 200
MNAKIADFGL SNMMSDGEFL RTSCGSPNYA APEVISGRLY AGPEVDIWSC
210 220 230 240 250
GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPDYLNRS VATLLMHMLQ
260 270 280 290 300
VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF
310 320 330 340 350
ECTESEVMNS LYSGDPQDQL AVAYHLIIDN RRIMNQASEF YLASSPPSGS
360 370 380 390 400
FMDDSAMHIP PGLKPHPERM PPLIADSPKA RCPLDALNTT KPKSLAVKKA
410 420 430 440 450
KWHLGIRSQS KACDIMAEVY RAMKQLGFEW KVVNAYHLRV RRKNPVTGNY
460 470 480 490 500
VKMSLQLYLV DSRSYLLDFK SIDDEVVEQR SGSSTPQRSC SAAGLHRARS
510 520 530 540 550
SFDSSTAENH SLSGSLTGSL TGSTLSSASP RLGSHTMDFF EMCASLITAL

AR
Length:552
Mass (Da):62,022
Last modified:July 27, 2011 - v3
Checksum:i020B11E2685BFE39
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti15H → D in BAE22188 (PubMed:16141072).Curated1
Sequence conflicti289D → V in BAC31746 (PubMed:16141072).Curated1
Sequence conflicti380A → E in BAE22188 (PubMed:16141072).Curated1
Sequence conflicti502F → Y in BAE22188 (PubMed:16141072).Curated1
Sequence conflicti506T → K in BAE22188 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL627307, AL929466 Genomic DNA Translation: CAM18832.1
AL929466, AL627307 Genomic DNA Translation: CAM24127.1
BC138565 mRNA Translation: AAI38566.1
BC138566 mRNA Translation: AAI38567.1
AK044030 mRNA Translation: BAC31746.1
AK134573 mRNA Translation: BAE22188.1
CCDSiCCDS18416.1
RefSeqiNP_835279.2, NM_178143.2
UniGeneiMm.48638

Genome annotation databases

EnsembliENSMUST00000030243; ENSMUSP00000030243; ENSMUSG00000028518
GeneIDi108079
KEGGimmu:108079
UCSCiuc008tyd.2 mouse

Similar proteinsi

Entry informationi

Entry nameiAAPK2_MOUSE
AccessioniPrimary (citable) accession number: Q8BRK8
Secondary accession number(s): B1ASQ8, Q3UYM4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 28, 2006
Last sequence update: July 27, 2011
Last modified: May 23, 2018
This is version 140 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

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