AAPK1_PIG
ID AAPK1_PIG Reviewed; 385 AA.
AC Q09136; B2MV24;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 02-SEP-2008, sequence version 2.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-1;
DE Short=AMPK subunit alpha-1;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:P54645};
DE AltName: Full=AMPK 63 kDa subunit;
DE AltName: Full=Acetyl-CoA carboxylase kinase;
DE Short=ACACA kinase;
DE EC=2.7.11.27 {ECO:0000250|UniProtKB:P54645};
DE AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase;
DE Short=HMGCR kinase;
DE EC=2.7.11.31 {ECO:0000250|UniProtKB:P54645};
DE AltName: Full=Tau-protein kinase PRKAA1;
DE EC=2.7.11.26 {ECO:0000250|UniProtKB:P54645};
DE Flags: Fragments;
GN Name=PRKAA1; Synonyms=AMPK1;
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 PROTEIN SEQUENCE OF 1-22; 73-87; 100-157; 222-240 AND 344-361, AND
RP FUNCTION.
RC TISSUE=Liver;
RX PubMed=7905477; DOI=10.1016/s0021-9258(17)41951-x;
RA Mitchelhill K.I., Stapleton D., Gao G., House C., Michell B., Katsis F.,
RA Witters L.A., Kemp B.E.;
RT "Mammalian AMP-activated protein kinase shares structural and functional
RT homology with the catalytic domain of yeast Snf1 protein kinase.";
RL J. Biol. Chem. 269:2361-2364(1994).
RN [2]
RP PROTEIN SEQUENCE OF 1-22; 73-88; 100-132; 144-156; 209-216; 221-255;
RP 256-270; 271-290; 291-300; 301-323; 324-342; 343-367 AND 368-385, AND
RP INDUCTION.
RC TISSUE=Liver;
RX PubMed=8557660; DOI=10.1074/jbc.271.2.611;
RA Stapleton D., Mitchelhill K.I., Gao G., Widmer J., Michell B.J., Teh T.,
RA House C.M., Fernandez C.S., Cox T., Witters L.A., Kemp B.E.;
RT "Mammalian AMP-activated protein kinase subfamily.";
RL J. Biol. Chem. 271:611-614(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 23-243.
RA Weber T.E.;
RT "Effect of dietary hemicellulose on growth and energy metabolism of growing
RT pigs.";
RL Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases.
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 (PubMed:7905477). In response to reduction
CC of intracellular ATP levels, AMPK activates energy-producing pathways
CC and inhibits energy-consuming processes: inhibits protein, carbohydrate
CC and lipid biosynthesis, as well as cell growth and proliferation. AMPK
CC acts via direct phosphorylation of metabolic enzymes, and by longer-
CC term effects via phosphorylation of transcription regulators (By
CC similarity). Regulates lipid synthesis by phosphorylating and
CC inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR
CC and LIPE; regulates fatty acid and cholesterol synthesis by
CC phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-
CC sensitive lipase (LIPE) enzymes, respectively (By similarity). Promotes
CC lipolysis of lipid droplets by mediating phosphorylation of isoform 1
CC of CHKA (CHKalpha2) (By similarity). Regulates insulin-signaling and
CC glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity).
CC AMPK stimulates glucose uptake in muscle by increasing the
CC translocation of the glucose transporter SLC2A4/GLUT4 to the plasma
CC membrane, possibly by mediating phosphorylation of TBC1D4/AS160 (By
CC similarity). Regulates transcription and chromatin structure by
CC phosphorylating transcription regulators involved in energy metabolism
CC such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP,
CC EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (By similarity).
CC Acts as a key regulator of glucose homeostasis in liver by
CC phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in
CC the cytoplasm. In response to stress, phosphorylates 'Ser-36' of
CC histone H2B (H2BS36ph), leading to promote transcription (By
CC similarity). Acts as a key regulator of cell growth and proliferation
CC by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient
CC limitation, negatively regulates the mTORC1 complex by phosphorylating
CC RPTOR component of the mTORC1 complex and by phosphorylating and
CC activating TSC2. In response to nutrient limitation, promotes autophagy
CC by phosphorylating and activating ATG1/ULK1. In that process also
CC activates WDR45/WIPI4. Phosphorylates CASP6, thereby preventing its
CC autoprocessing and subsequent activation (By similarity). In response
CC to nutrient limitation, phosphorylates transcription factor FOXO3
CC promoting FOXO3 mitochondrial import (By similarity). Also acts as a
CC regulator of cellular polarity by remodeling the actin cytoskeleton;
CC probably by indirectly activating myosin (By similarity). AMPK also
CC acts as a regulator of circadian rhythm by mediating phosphorylation of
CC CRY1, leading to destabilize it. May regulate the Wnt signaling pathway
CC by phosphorylating CTNNB1, leading to stabilize it (By similarity).
CC Also has tau-protein kinase activity: in response to amyloid beta A4
CC protein (APP) exposure, activated by CAMKK2, leading to phosphorylation
CC of MAPT/TAU; however the relevance of such data remains unclear in vivo
CC (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and
CC SLC12A1 (By similarity). {ECO:0000250|UniProtKB:P54645,
CC ECO:0000250|UniProtKB:Q13131, ECO:0000250|UniProtKB:Q5EG47,
CC ECO:0000269|PubMed:7905477}.
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:P54645};
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:P54645};
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:P54645};
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:P54645};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[tau protein] = ADP + H(+) + O-phospho-L-seryl-
CC [tau protein]; Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[tau protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[tau protein]; Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.26; Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-133. Binding
CC of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3)
CC results in allosteric activation, inducing phosphorylation on Thr-133.
CC AMP-binding to gamma subunit also sustains activity by preventing
CC dephosphorylation of Thr-133. ADP also stimulates Thr-133
CC phosphorylation, without stimulating already phosphorylated AMPK. ATP
CC promotes dephosphorylation of Thr-133, 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 (By similarity). {ECO:0000250|UniProtKB:Q13131}.
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.
CC {ECO:0000250|UniProtKB:Q13131}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q13131}. Nucleus
CC {ECO:0000250|UniProtKB:Q13131}. Note=In response to stress, recruited
CC by p53/TP53 to specific promoters. {ECO:0000250|UniProtKB:Q13131}.
CC -!- INDUCTION: By AMP. {ECO:0000269|PubMed:8557660}.
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:Q5EG47}.
CC -!- PTM: Phosphorylated at Thr-133 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39. Also
CC phosphorylated at Thr-133 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-133, but at a much lower
CC level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and
CC PP2C). Phosphorylated by ULK1 and ULK2; leading to negatively regulate
CC AMPK activity and suggesting the existence of a regulatory feedback
CC loop between ULK1, ULK2 and AMPK (By similarity). Dephosphorylated by
CC PPM1A and PPM1B (By similarity). {ECO:0000250|UniProtKB:Q13131}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. SNF1 subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; EU622639; ACC78144.1; -; mRNA.
DR PIR; A49958; A49958.
DR PeptideAtlas; Q09136; -.
DR PRIDE; Q09136; -.
DR InParanoid; Q09136; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0031588; C:nucleotide-activated protein kinase complex; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0035174; F:histone serine kinase activity; ISS:UniProtKB.
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:0050321; F:tau-protein kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISS:UniProtKB.
DR GO; GO:0031669; P:cellular response to nutrient levels; ISS:UniProtKB.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0055089; P:fatty acid homeostasis; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:1905691; P:lipid droplet disassembly; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:1903944; P:negative regulation of hepatocyte apoptotic process; ISS:UniProtKB.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; ISS:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISS:UniProtKB.
DR GO; GO:1990044; P:protein localization to lipid droplet; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0010332; P:response to gamma radiation; ISS:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF103243; SSF103243; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Autophagy; Biological rhythms; Cholesterol biosynthesis;
KW Cholesterol metabolism; Chromatin regulator; Cytoplasm;
KW Direct protein sequencing; Fatty acid biosynthesis; Fatty acid metabolism;
KW Kinase; Lipid biosynthesis; Lipid metabolism; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation;
KW Wnt signaling pathway.
FT CHAIN <1..>385
FT /note="5'-AMP-activated protein kinase catalytic subunit
FT alpha-1"
FT /id="PRO_0000085591"
FT DOMAIN <1..229
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 252..297
FT /note="AIS"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT ACT_SITE 100
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 15..>22
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 14
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 133
FT /note="Phosphothreonine; by LKB1 and CaMKK2"
FT /evidence="ECO:0000250|UniProtKB:Q5EG47"
FT MOD_RES 219
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 276
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 277
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 281
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 289
FT /note="Phosphothreonine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 298
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 353
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 383
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT NON_CONS 22..23
FT /evidence="ECO:0000305"
FT NON_CONS 157..158
FT /evidence="ECO:0000305"
FT NON_CONS 255..256
FT /evidence="ECO:0000305"
FT NON_CONS 270..271
FT /evidence="ECO:0000305"
FT NON_CONS 290..291
FT /evidence="ECO:0000305"
FT NON_CONS 300..301
FT /evidence="ECO:0000305"
FT NON_CONS 323..324
FT /evidence="ECO:0000305"
FT NON_CONS 342..343
FT /evidence="ECO:0000305"
FT NON_CONS 367..368
FT /evidence="ECO:0000305"
FT NON_TER 1
FT NON_TER 385
SQ SEQUENCE 385 AA; 44226 MW; A9B4BC0C935A85A6 CRC64;
DGRVKIGHYI LGDTLGVGTF GKRREIQNLK LFRHPHIIKL YQVISTPSDI FMVMEYVSGG
ELFDYICKNG RLDEKESRRL FQQILSGVDY CHRHMVVHRD LKPENVLLDA HMNAKIADFG
LSNMMSDGEF LRTSCGSPNY AAPEVISGRL YAGPEVDIWS SGVILYALLC GTLPFDDDHV
PTLFKKICDG IFYTPQYLNP SVISLLKHML QVDPMKRATI KDIREHEWFK QDLPKYLFPE
DPSYSXTMID DEALKQDPLA VAYHLIIDNR DFYLATSPPD SFLDDHHLTR VPFLVAETPR
DELNPQKXKH QGVRKAKXHL GIRQLDYEXK VVNPYYLRVR RKKMSLQLYQ VDSRTYLLDF
RSIDDXIDAE AQGKSSEASL TXSVT
