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Protein

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

Gene

Prkaa2

Organism
Rattus norvegicus (Rat)
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. 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

Activity 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)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

GO - Biological processi

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 5301
2.7.11.31 5301
SABIO-RKiQ09137

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620893 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

Chemistry databases

ChEMBLiCHEMBL4637

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000855971 – 5525'-AMP-activated protein kinase catalytic subunit alpha-2Add BLAST552

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei172Phosphothreonine; by LKB1 and CaMKK25 Publications1
Modified residuei258Phosphothreonine1 Publication1
Modified residuei377PhosphoserineCombined sources1
Modified residuei491Phosphoserine1 Publication1

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
PhosphoSitePlusiQ09137

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-protein interaction databases

BioGridi249382, 7 interactors
CORUMiQ09137
IntActiQ09137, 1 interactor
STRINGi10116.ENSRNOP00000010680

Chemistry databases

BindingDBiQ09137

Structurei

3D structure databases

ProteinModelPortaliQ09137
SMRiQ09137
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
HOGENOMiHOG000233016
HOVERGENiHBG050432
InParanoidiQ09137
KOiK07198
PhylomeDBiQ09137

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

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G3V715G3V715_RAT
Non-specific serine/threonine prote...
Prkaa2 rCG_53426
552Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti355M → S in AAA85033 (PubMed:7718624).Curated1
Sequence conflicti462N → D in AAA85033 (PubMed:7718624).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_00494932 – 388Missing in isoform Short. 1 PublicationAdd BLAST357
Alternative sequenceiVSP_004950392 – 552Missing in isoform Short. 1 PublicationAdd BLAST161

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

Similar proteinsi

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
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249382, 7 interactors
CORUMiQ09137
IntActiQ09137, 1 interactor
STRINGi10116.ENSRNOP00000010680

Chemistry databases

BindingDBiQ09137
ChEMBLiCHEMBL4637

PTM databases

iPTMnetiQ09137
PhosphoSitePlusiQ09137

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
SABIO-RKiQ09137

Miscellaneous databases

PROiPR:Q09137

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
ProtoNetiSearch...

Entry informationi

Entry nameiAAPK2_RAT
AccessioniPrimary (citable) accession number: Q09137
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: November 7, 2018
This is version 164 of the entry and version 1 of the sequence. See 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
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