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UniProtKB - P54646 (AAPK2_HUMAN)

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Protein

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

Gene

PRKAA2

Organism
Homo sapiens (Human)
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 (PubMed:25687571). 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 (By similarity).By similarity13 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. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). 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 sitei45ATPPROSITE-ProRule annotation1
Active sitei139Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi22 – 30ATPPROSITE-ProRule annotation9

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

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

BRENDAi2.7.11.1 2681
ReactomeiR-HSA-1445148 Translocation of GLUT4 to the plasma membrane
R-HSA-1632852 Macroautophagy
R-HSA-163680 AMPK inhibits chREBP transcriptional activation activity
R-HSA-200425 Import of palmitoyl-CoA into the mitochondrial matrix
R-HSA-2151209 Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-380972 Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897 TP53 Regulates Metabolic Genes
R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation
SignaLinkiP54646
SIGNORiP54646

Protein family/group databases

TCDBi8.A.104.1.1 the 5'-amp-activated protein kinase (ampk) family

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:PRKAA2
Synonyms:AMPK, AMPK2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000162409.10
HGNCiHGNC:9377 PRKAA2
MIMi600497 gene
neXtProtiNX_P54646

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

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi172T → D: Phosphomimetic mutant. 1

Organism-specific databases

DisGeNETi5563
OpenTargetsiENSG00000162409
PharmGKBiPA33745

Chemistry databases

ChEMBLiCHEMBL2116
DrugBankiDB00945 Acetylsalicylic acid
GuidetoPHARMACOLOGYi1542

Polymorphism and mutation databases

BioMutaiPRKAA2
DMDMi20178276

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000855941 – 5525'-AMP-activated protein kinase catalytic subunit alpha-2Add BLAST552

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei172Phosphothreonine; by LKB1 and CaMKK21 Publication1
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).2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP54646
MaxQBiP54646
PaxDbiP54646
PeptideAtlasiP54646
PRIDEiP54646
ProteomicsDBi56689

PTM databases

iPTMnetiP54646
PhosphoSitePlusiP54646

Expressioni

Gene expression databases

BgeeiENSG00000162409
CleanExiHS_PRKAA2
ExpressionAtlasiP54646 baseline and differential
GenevisibleiP54646 HS

Organism-specific databases

HPAiHPA044540

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. Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).2 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi111550, 89 interactors
CORUMiP54646
DIPiDIP-39796N
IntActiP54646, 139 interactors
MINTiP54646
STRINGi9606.ENSP00000360290

Chemistry databases

BindingDBiP54646

Structurei

Secondary structure

1552
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi16 – 24Combined sources9
Beta strandi26 – 35Combined sources10
Turni36 – 38Combined sources3
Beta strandi41 – 48Combined sources8
Helixi49 – 54Combined sources6
Helixi58 – 69Combined sources12
Beta strandi79 – 84Combined sources6
Beta strandi86 – 94Combined sources9
Helixi101 – 108Combined sources8
Helixi113 – 133Combined sources21
Helixi142 – 144Combined sources3
Beta strandi145 – 147Combined sources3
Beta strandi153 – 155Combined sources3
Helixi160 – 162Combined sources3
Helixi177 – 179Combined sources3
Helixi183 – 185Combined sources3
Helixi192 – 209Combined sources18
Helixi219 – 228Combined sources10
Beta strandi235 – 237Combined sources3
Helixi239 – 248Combined sources10
Helixi253 – 255Combined sources3
Helixi259 – 264Combined sources6
Helixi266 – 269Combined sources4
Helixi274 – 276Combined sources3
Helixi283 – 286Combined sources4
Helixi290 – 299Combined sources10
Helixi304 – 312Combined sources9
Helixi319 – 335Combined sources17
Helixi338 – 341Combined sources4
Beta strandi403 – 408Combined sources6
Helixi412 – 426Combined sources15
Beta strandi429 – 434Combined sources6
Beta strandi437 – 443Combined sources7
Turni445 – 447Combined sources3
Beta strandi450 – 459Combined sources10
Beta strandi461 – 463Combined sources3
Beta strandi465 – 472Combined sources8
Helixi535 – 549Combined sources15

3D structure databases

ProteinModelPortaliP54646
SMRiP54646
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP54646

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.

Sequence similaritiesi

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.Curated

Phylogenomic databases

eggNOGiKOG0586 Eukaryota
ENOG410XNQ0 LUCA
GeneTreeiENSGT00900000140868
HOGENOMiHOG000233016
HOVERGENiHBG050432
KOiK07198
OMAiRWHFGIR
PhylomeDBiP54646
TreeFamiTF314032

Family and domain databases

CDDicd12200 AMPKA2_C, 1 hit
InterProiView protein in InterPro
IPR032270 AMPK_C
IPR039148 AMPKA2_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.

P54646-1 [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 VEEMEARRLF QQILSAVDYC HRHMVVHRDL KPENVLLDAH 
       160        170        180        190        200
MNAKIADFGL SNMMSDGEFL RTSCGSPNYA APEVISGRLY AGPEVDIWSC 
       210        220        230        240        250
GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPEYLNRS 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 KPYDIMAEVY RAMKQLDFEW KVVNAYHLRV RRKNPVTGNY 
       460        470        480        490        500
VKMSLQLYLV DNRSYLLDFK SIDDEVVEQR SGSSTPQRSC SAAGLHRPRS 
       510        520        530        540        550
SFDSTTAESH SLSGSLTGSL TGSTLSSVSP RLGSHTMDFF EMCASLITTL 

AR
Length:552
Mass (Da):62,320
Last modified:April 16, 2002 - v2
Checksum:iC46AAFC1D5104975
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti180A → T in AAA64745 (PubMed:7959015).Curated1
Sequence conflicti271D → G in AAA64745 (PubMed:7959015).Curated1
Sequence conflicti403 – 404HL → RQ in AAA64745 (PubMed:7959015).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_035623371P → T in breast cancer samples; infiltrating ductal carcinoma; somatic mutation. 2 Publications1
Natural variantiVAR_040355407R → Q in a gastric adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_035624523S → G in a breast cancer sample; somatic mutation. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U06454 mRNA Translation: AAA64745.1
AL035705 Genomic DNA No translation available.
BC069680 mRNA Translation: AAH69680.1
BC069740 mRNA Translation: AAH69740.1
BC069823 mRNA Translation: AAH69823.1
CCDSiCCDS605.1
PIRiS51025
RefSeqiNP_006243.2, NM_006252.3
UniGeneiHs.437039

Genome annotation databases

EnsembliENST00000371244; ENSP00000360290; ENSG00000162409
GeneIDi5563
KEGGihsa:5563
UCSCiuc001cyk.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiAAPK2_HUMAN
AccessioniPrimary (citable) accession number: P54646
Secondary accession number(s): Q9H1E8, Q9UD43
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: April 16, 2002
Last modified: July 18, 2018
This is version 188 of the entry and version 2 of the sequence. See 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: 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

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