AAPK2_PIG
ID AAPK2_PIG Reviewed; 552 AA.
AC Q28948; Q7YRX9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 13-SEP-2005, sequence version 2.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-2;
DE Short=AMPK subunit alpha-2;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q09137};
DE AltName: Full=Acetyl-CoA carboxylase kinase;
DE Short=ACACA kinase;
DE EC=2.7.11.27 {ECO:0000250|UniProtKB:Q09137};
DE AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase;
DE Short=HMGCR kinase;
DE EC=2.7.11.31 {ECO:0000250|UniProtKB:Q09137};
GN Name=PRKAA2; Synonyms=AMPK2;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Kim T.-H., Choi B.-H., Park E.-W., Jeon J.-T., Park H.-S., Cheong I.-C.;
RT "Molecular cloning and characterization of the porcine AMP-activated
RT protein kinase alpha 2 (AMPKa2) gene.";
RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 16-144.
RC TISSUE=Liver;
RX PubMed=7718624; DOI=10.1016/0167-4889(94)00222-z;
RA Gao G., Widmer J., Stapleton D., Teh T., Cox T., Kemp B.E., Witters L.A.;
RT "Catalytic subunits of the porcine and rat 5'-AMP-activated protein kinase
RT are members of the SNF1 protein kinase family.";
RL Biochim. Biophys. Acta 1266:73-82(1995).
CC -!- FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an
CC energy sensor protein kinase that plays a key role in regulating
CC cellular energy metabolism. In response to reduction of intracellular
CC ATP levels, AMPK activates energy-producing pathways and inhibits
CC energy-consuming processes: inhibits protein, carbohydrate and lipid
CC biosynthesis, as well as cell growth and proliferation. AMPK acts via
CC direct phosphorylation of metabolic enzymes, and by longer-term effects
CC via phosphorylation of transcription regulators. Regulates lipid
CC synthesis by phosphorylating and inactivating lipid metabolic enzymes
CC such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and
CC cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA
CC and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively
CC (By similarity). Promotes lipolysis of lipid droplets by mediating
CC phosphorylation of isoform 1 of CHKA (CHKalpha2) (By similarity).
CC Regulates insulin-signaling and glycolysis by phosphorylating IRS1,
CC PFKFB2 and PFKFB3 (By similarity). Involved in insulin receptor/INSR
CC internalization (By similarity). AMPK stimulates glucose uptake in
CC muscle by increasing the translocation of the glucose transporter
CC SLC2A4/GLUT4 to the plasma membrane, possibly by mediating
CC phosphorylation of TBC1D4/AS160 (By similarity). Regulates
CC transcription and chromatin structure by phosphorylating transcription
CC regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3,
CC histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53,
CC SREBF1, SREBF2 and PPARGC1A (By similarity). Acts as a key regulator of
CC glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to
CC CRTC2/TORC2 sequestration in the cytoplasm. In response to stress,
CC phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote
CC transcription (By similarity). Acts as a key regulator of cell growth
CC and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in
CC response to nutrient limitation, negatively regulates the mTORC1
CC complex by phosphorylating RPTOR component of the mTORC1 complex and by
CC phosphorylating and activating TSC2. In response to nutrient
CC limitation, promotes autophagy by phosphorylating and activating
CC ATG1/ULK1. In that process also activates WDR45/WIPI4. Phosphorylates
CC CASP6, thereby preventing its autoprocessing and subsequent activation
CC (By similarity). AMPK also acts as a regulator of circadian rhythm by
CC mediating phosphorylation of CRY1, leading to destabilize it. May
CC regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading
CC to stabilize it (By similarity). Also acts as a regulator of cellular
CC polarity by remodeling the actin cytoskeleton; probably by indirectly
CC activating myosin. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and
CC SLC12A1 (By similarity). Plays an important role in the differential
CC regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and
CC UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and
CC PIK3R4) complexes, in response to glucose starvation. Can inhibit the
CC non-autophagy complex by phosphorylating PIK3C3 and can activate the
CC pro-autophagy complex by phosphorylating BECN1 (By similarity).
CC {ECO:0000250|UniProtKB:P54646, ECO:0000250|UniProtKB:Q09137,
CC ECO:0000250|UniProtKB:Q8BRK8}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000250|UniProtKB:Q09137};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:Q09137};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[acetyl-CoA carboxylase] = ADP + H(+) + O-
CC phospho-L-seryl-[acetyl-CoA carboxylase]; Xref=Rhea:RHEA:20333,
CC Rhea:RHEA-COMP:13722, Rhea:RHEA-COMP:13723, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421,
CC ChEBI:CHEBI:456216; EC=2.7.11.27;
CC Evidence={ECO:0000250|UniProtKB:Q09137};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A
CC reductase] = ADP + H(+) + O-phospho-L-seryl-[3-hydroxy-3-
CC methylglutaryl-coenzyme A reductase]; Xref=Rhea:RHEA:23172,
CC Rhea:RHEA-COMP:13692, Rhea:RHEA-COMP:13693, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421,
CC ChEBI:CHEBI:456216; EC=2.7.11.31;
CC Evidence={ECO:0000250|UniProtKB:Q09137};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000305};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-172. Binding
CC of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3)
CC results in allosteric activation, inducing phosphorylation on Thr-172.
CC AMP-binding to gamma subunit also sustains activity by preventing
CC dephosphorylation of Thr-172. ADP also stimulates Thr-172
CC phosphorylation, without stimulating already phosphorylated AMPK. ATP
CC promotes dephosphorylation of Thr-172, rendering the enzyme inactive.
CC Under physiological conditions AMPK mainly exists in its inactive form
CC in complex with ATP, which is much more abundant than AMP. Selectively
CC inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-
CC pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a
CC natural polyphenol present in red wine, and S17834, a synthetic
CC polyphenol. Salicylate/aspirin directly activates kinase activity,
CC primarily by inhibiting Thr-172 dephosphorylation (By similarity).
CC {ECO:0000250|UniProtKB:P54646}.
CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1
CC or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic
CC subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2 (By
CC similarity). Interacts with DUSP29 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:Q8BRK8}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BRK8}. Nucleus
CC {ECO:0000250|UniProtKB:P54646}. Note=In response to stress, recruited
CC by p53/TP53 to specific promoters. {ECO:0000250|UniProtKB:P54646}.
CC -!- DOMAIN: The AIS (autoinhibitory sequence) region shows some sequence
CC similarity with the ubiquitin-associated domains and represses kinase
CC activity. {ECO:0000250|UniProtKB:Q13131}.
CC -!- PTM: Ubiquitinated. {ECO:0000250|UniProtKB:Q8BRK8}.
CC -!- PTM: Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39. Also
CC phosphorylated at Thr-172 by CAMKK2; triggered by a rise in
CC intracellular calcium ions, without detectable changes in the AMP/ATP
CC ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level.
CC Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C).
CC Phosphorylated by ULK1; leading to negatively regulate AMPK activity
CC and suggesting the existence of a regulatory feedback loop between ULK1
CC and AMPK (By similarity). Dephosphorylated by PPM1A and PPM1B at Thr-
CC 172 (mediated by STK11/LKB1) (By similarity).
CC {ECO:0000250|UniProtKB:P54646}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. SNF1 subfamily. {ECO:0000305}.
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DR EMBL; AY159788; AAO17789.1; -; mRNA.
DR EMBL; U12148; AAA85034.1; -; mRNA.
DR RefSeq; NP_999431.1; NM_214266.1.
DR AlphaFoldDB; Q28948; -.
DR BMRB; Q28948; -.
DR SMR; Q28948; -.
DR STRING; 9823.ENSSSCP00000004154; -.
DR iPTMnet; Q28948; -.
DR PaxDb; Q28948; -.
DR PeptideAtlas; Q28948; -.
DR Ensembl; ENSSSCT00000055782; ENSSSCP00000055569; ENSSSCG00000036145.
DR Ensembl; ENSSSCT00025002517; ENSSSCP00025000866; ENSSSCG00025001949.
DR Ensembl; ENSSSCT00030025452; ENSSSCP00030011356; ENSSSCG00030018428.
DR Ensembl; ENSSSCT00035066490; ENSSSCP00035026961; ENSSSCG00035049899.
DR Ensembl; ENSSSCT00040103801; ENSSSCP00040047156; ENSSSCG00040074948.
DR Ensembl; ENSSSCT00045022440; ENSSSCP00045015458; ENSSSCG00045013178.
DR Ensembl; ENSSSCT00050090786; ENSSSCP00050039011; ENSSSCG00050066634.
DR Ensembl; ENSSSCT00055018344; ENSSSCP00055014432; ENSSSCG00055009404.
DR Ensembl; ENSSSCT00060059516; ENSSSCP00060025496; ENSSSCG00060043886.
DR Ensembl; ENSSSCT00065073966; ENSSSCP00065032216; ENSSSCG00065053967.
DR Ensembl; ENSSSCT00065073973; ENSSSCP00065032221; ENSSSCG00065053967.
DR Ensembl; ENSSSCT00070060625; ENSSSCP00070051667; ENSSSCG00070030147.
DR Ensembl; ENSSSCT00070060626; ENSSSCP00070051668; ENSSSCG00070030147.
DR GeneID; 397504; -.
DR KEGG; ssc:397504; -.
DR CTD; 5563; -.
DR VGNC; VGNC:91798; PRKAA2.
DR eggNOG; KOG0583; Eukaryota.
DR GeneTree; ENSGT00940000156945; -.
DR InParanoid; Q28948; -.
DR OMA; KALNYEW; -.
DR OrthoDB; 1127668at2759; -.
DR BRENDA; 2.7.11.1; 6170.
DR Proteomes; UP000008227; Chromosome 6.
DR Proteomes; UP000314985; Chromosome 6.
DR Bgee; ENSSSCG00000036145; Expressed in skeletal muscle tissue and 43 other tissues.
DR ExpressionAtlas; Q28948; baseline and differential.
DR GO; GO:0030424; C:axon; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0010494; C:cytoplasmic stress granule; IEA:Ensembl.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0016607; C:nuclear speck; IEA:Ensembl.
DR GO; GO:0031588; C:nucleotide-activated protein kinase complex; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0050405; F:[acetyl-CoA carboxylase] kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0047322; F:[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004679; F:AMP-activated protein kinase activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0035174; F:histone serine kinase activity; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:Ensembl.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0071277; P:cellular response to calcium ion; IEA:Ensembl.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0034599; P:cellular response to oxidative stress; IEA:Ensembl.
DR GO; GO:0071380; P:cellular response to prostaglandin E stimulus; IEA:Ensembl.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:1905691; P:lipid droplet disassembly; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IEA:Ensembl.
DR GO; GO:1904428; P:negative regulation of tubulin deacetylation; IEA:Ensembl.
DR GO; GO:0010508; P:positive regulation of autophagy; IEA:Ensembl.
DR GO; GO:2000758; P:positive regulation of peptidyl-lysine acetylation; IEA:Ensembl.
DR GO; GO:1903829; P:positive regulation of protein localization; IEA:Ensembl.
DR GO; GO:1990044; P:protein localization to lipid droplet; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; IEA:Ensembl.
DR GO; GO:0016241; P:regulation of macroautophagy; ISS:UniProtKB.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0062028; P:regulation of stress granule assembly; IEA:Ensembl.
DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd12200; AMPKA2_C; 1.
DR CDD; cd14404; UBA_AID_AAPK2; 1.
DR InterPro; IPR032270; AMPK_C.
DR InterPro; IPR039148; AMPKA2_C.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR028783; PRKAA2.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF16579; AdenylateSensor; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF103243; SSF103243; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Autophagy; Biological rhythms; Cholesterol biosynthesis;
KW Cholesterol metabolism; Chromatin regulator; Cytoplasm;
KW Fatty acid biosynthesis; Fatty acid metabolism; Kinase; Lipid biosynthesis;
KW Lipid metabolism; Magnesium; Metal-binding; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transcription; Transcription regulation; Transferase;
KW Ubl conjugation; Wnt signaling pathway.
FT CHAIN 1..552
FT /note="5'-AMP-activated protein kinase catalytic subunit
FT alpha-2"
FT /id="PRO_0000085595"
FT DOMAIN 16..268
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 291..376
FT /note="AIS"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT REGION 478..519
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 502..519
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 139
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 22..30
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 45
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 172
FT /note="Phosphothreonine; by LKB1 and CaMKK2"
FT /evidence="ECO:0000250|UniProtKB:P54646"
FT MOD_RES 258
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q09137"
FT MOD_RES 377
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P54646"
FT MOD_RES 491
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q09137"
FT CONFLICT 17
FT /note="V -> M (in Ref. 2; AAA85034)"
FT /evidence="ECO:0000305"
FT CONFLICT 30
FT /note="V -> E (in Ref. 2; AAA85034)"
FT /evidence="ECO:0000305"
FT CONFLICT 144
FT /note="N -> K (in Ref. 2; AAA85034)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 552 AA; 62325 MW; 628C2529B5D07B02 CRC64;
MAEKQKHDGR VKIGHYVLGD TLGVGTFGKV KIGEHQLTGH KVAVKILNRQ KIRSLDVVGK
IKREIQNLKL FRHPHIIKLY QVISTPTDFF MVMEYVSGGE LFDYICKHGR VEEMEARRLF
QQILSAVDYC HRHMVVHRDL KPENVLLDAQ MNAKIADFGL SNMMSDGEFL RTSCGSPNYA
APEVISGRLY AGPEVDIWSC GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPEYLNRS
VATLLMHMLQ VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF
ECTESEVMNS LYSGDPQDQL AVAYHLVIDN RRIMNQASEF YLASSPPTGS FMDDSAMHIP
PGLKPHPERM PPLIADSPKA RCPLDALNTT KPKSLAVKKA KWHLGIRSQS KPYDIMAEVY
RAMKQLDFEW KVVNAYHLRV RRKNPVTGNY VKMSLQLYLV DNRSYLLDFK SIDDEVLEQR
SGSSTPQRSC SAAGLHRPRS SLDSVTAESH SLSGSLSGSL TGSMLPSVPP RLGSHTMDFF
EMCASLITTL AR
