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Protein

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

Gene

Prkaa2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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. 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 similarity11 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.2 Publications
ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate.1 Publication
ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate.1 Publication

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 (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei45 – 451ATPPROSITE-ProRule annotation
Active sitei139 – 1391Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi22 – 309ATPPROSITE-ProRule annotation

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: RGD
  • chromatin binding Source: UniProtKB
  • histone serine kinase activity Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • protein binding, bridging Source: RGD
  • protein kinase activity Source: RGD
  • protein serine/threonine kinase activity Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Autophagy, 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

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1. 5301.
2.7.11.31. 5301.
ReactomeiR-RNO-163680. AMPK inhibits chREBP transcriptional activation activity.
SABIO-RKQ09137.

Names & Taxonomyi

Protein namesi
Recommended name:
5'-AMP-activated protein kinase catalytic subunit alpha-2 (EC:2.7.11.12 Publications)
Short name:
AMPK subunit alpha-2
Alternative name(s):
Acetyl-CoA carboxylase kinase (EC:2.7.11.271 Publication)
Short name:
ACACA kinase
Hydroxymethylglutaryl-CoA reductase kinase (EC:2.7.11.311 Publication)
Short name:
HMGCR kinase
Gene namesi
Name:Prkaa2
Synonyms:Ampk, Ampk2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620893. Prkaa2.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: In response to stress, recruited by p53/TP53 to specific promoters.By similarity

GO - Cellular componenti

  • apical plasma membrane Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleotide-activated protein kinase complex Source: RGD
  • nucleus Source: GO_Central
  • protein complex Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Chemistry

ChEMBLiCHEMBL4637.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 5525525'-AMP-activated protein kinase catalytic subunit alpha-2PRO_0000085597Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei172 – 1721Phosphothreonine; by LKB1 and CaMKK25 Publications
Modified residuei258 – 2581Phosphothreonine1 Publication
Modified residuei377 – 3771PhosphoserineCombined sources
Modified residuei491 – 4911Phosphoserine1 Publication

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

PaxDbiQ09137.
PRIDEiQ09137.

PTM databases

iPTMnetiQ09137.
PhosphoSiteiQ09137.

Expressioni

Tissue specificityi

Skeletal muscle, lower levels in liver, heart and kidney.

Inductioni

By AMP.

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 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).1 Publication

GO - Molecular functioni

  • protein binding, bridging Source: RGD

Protein-protein interaction databases

BioGridi249382. 7 interactions.
IntActiQ09137. 1 interaction.
STRINGi10116.ENSRNOP00000010680.

Chemistry

BindingDBiQ09137.

Structurei

3D structure databases

ProteinModelPortaliQ09137.
SMRiQ09137. Positions 10-278, 402-485.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini16 – 268253Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni291 – 37686AISBy similarityAdd
BLAST

Domaini

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

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0586. Eukaryota.
ENOG410XNQ0. LUCA.
HOGENOMiHOG000233016.
HOVERGENiHBG050432.
InParanoidiQ09137.
KOiK07198.
PhylomeDBiQ09137.

Family and domain databases

InterProiIPR032270. AMPK_C.
IPR028375. KA1/Ssp2_C.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF16579. AdenylateSensor. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF103243. SSF103243. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Long (identifier: Q09137-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« 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 FYIPEYLNRS IATLLMHMLQ
260 270 280 290 300
VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF
310 320 330 340 350
ECTESEVMNS LYSGDPQDQL AVAYHLIIDN RRIMNQASEF YLASSPPTGS
360 370 380 390 400
FMDDMAMHIP 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
SVDSSTAENH SLSGSLTGSL TGSTLSSASP RLGSHTMDFF EMCASLITAL

AR
Length:552
Mass (Da):62,258
Last modified:February 1, 1995 - v1
Checksum:i2829E07F674D89B1
GO
Isoform Short (identifier: Q09137-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     32-388: Missing.
     392-552: Missing.

Note: Lacks the sequence parts essential for kinase activity and is therefore inactive.
Show »
Length:34
Mass (Da):3,700
Checksum:i4BF6E5CF5CF23F3B
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti355 – 3551M → S in AAA85033 (PubMed:7718624).Curated
Sequence conflicti462 – 4621N → D in AAA85033 (PubMed:7718624).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei32 – 388357Missing in isoform Short. 1 PublicationVSP_004949Add
BLAST
Alternative sequencei392 – 552161Missing in isoform Short. 1 PublicationVSP_004950Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z29486 mRNA. Translation: CAA82620.1.
U12149 mRNA. Translation: AAA85033.1.
PIRiA53621.
RefSeqiNP_076481.1. NM_023991.1. [Q09137-1]
UniGeneiRn.64583.

Genome annotation databases

GeneIDi78975.
KEGGirno:78975.
UCSCiRGD:620893. rat. [Q09137-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Z29486 mRNA. Translation: CAA82620.1.
U12149 mRNA. Translation: AAA85033.1.
PIRiA53621.
RefSeqiNP_076481.1. NM_023991.1. [Q09137-1]
UniGeneiRn.64583.

3D structure databases

ProteinModelPortaliQ09137.
SMRiQ09137. Positions 10-278, 402-485.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249382. 7 interactions.
IntActiQ09137. 1 interaction.
STRINGi10116.ENSRNOP00000010680.

Chemistry

BindingDBiQ09137.
ChEMBLiCHEMBL4637.

PTM databases

iPTMnetiQ09137.
PhosphoSiteiQ09137.

Proteomic databases

PaxDbiQ09137.
PRIDEiQ09137.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi78975.
KEGGirno:78975.
UCSCiRGD:620893. rat. [Q09137-1]

Organism-specific databases

CTDi5563.
RGDi620893. Prkaa2.

Phylogenomic databases

eggNOGiKOG0586. Eukaryota.
ENOG410XNQ0. LUCA.
HOGENOMiHOG000233016.
HOVERGENiHBG050432.
InParanoidiQ09137.
KOiK07198.
PhylomeDBiQ09137.

Enzyme and pathway databases

BRENDAi2.7.11.1. 5301.
2.7.11.31. 5301.
ReactomeiR-RNO-163680. AMPK inhibits chREBP transcriptional activation activity.
SABIO-RKQ09137.

Miscellaneous databases

PROiQ09137.

Family and domain databases

InterProiIPR032270. AMPK_C.
IPR028375. KA1/Ssp2_C.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF16579. AdenylateSensor. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF103243. SSF103243. 1 hit.
SSF56112. 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 nameiAAPK2_RAT
AccessioniPrimary (citable) accession number: Q09137
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: July 6, 2016
This is version 150 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. 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.