AAPK1_PONAB
ID AAPK1_PONAB Reviewed; 554 AA.
AC Q5RDH5;
DT 13-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 28-JUL-2009, sequence version 2.
DT 03-AUG-2022, entry version 112.
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=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: Fragment;
GN Name=PRKAA1;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) 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. 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 (By similarity).
CC Regulates lipid synthesis by phosphorylating and inactivating lipid
CC metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates
CC fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA
CC carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE)
CC enzymes, respectively (By similarity). Promotes lipolysis of lipid
CC droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2)
CC (By similarity). Regulates insulin-signaling and glycolysis by
CC phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). AMPK
CC stimulates glucose uptake in muscle by increasing the translocation of
CC the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly
CC by mediating 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). In response to nutrient limitation, phosphorylates
CC transcription factor FOXO3 promoting FOXO3 mitochondrial import (By
CC similarity). Also acts as a regulator of cellular polarity by
CC remodeling the actin cytoskeleton; probably by indirectly activating
CC myosin (By similarity). AMPK also acts as a regulator of circadian
CC rhythm by mediating phosphorylation of CRY1, leading to destabilize it.
CC May regulate the Wnt signaling pathway by phosphorylating CTNNB1,
CC leading to stabilize it (By similarity). Also has tau-protein kinase
CC activity: in response to amyloid beta A4 protein (APP) exposure,
CC activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however
CC the relevance of such data remains unclear in vivo (By similarity).
CC Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (By
CC similarity). {ECO:0000250|UniProtKB:P54645,
CC ECO:0000250|UniProtKB:Q13131, ECO:0000250|UniProtKB:Q5EG47}.
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-183. Binding
CC of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3)
CC results in allosteric activation, inducing phosphorylation on Thr-183.
CC AMP-binding to gamma subunit also sustains activity by preventing
CC dephosphorylation of Thr-183. ADP also stimulates Thr-183
CC phosphorylation, without stimulating already phosphorylated AMPK. ATP
CC promotes dephosphorylation of Thr-183, 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 -!- 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-183 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39. Also
CC phosphorylated at Thr-183 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-183, 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 -!- SEQUENCE CAUTION:
CC Sequence=CAH90182.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; CR857935; CAH90182.1; ALT_INIT; mRNA.
DR RefSeq; NP_001127249.1; NM_001133777.1.
DR AlphaFoldDB; Q5RDH5; -.
DR SMR; Q5RDH5; -.
DR STRING; 9601.ENSPPYP00000017227; -.
DR GeneID; 100174304; -.
DR KEGG; pon:100174304; -.
DR CTD; 5562; -.
DR eggNOG; KOG0583; Eukaryota.
DR InParanoid; Q5RDH5; -.
DR Proteomes; UP000001595; 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: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: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 CDD; cd12199; AMPKA1_C; 1.
DR CDD; cd14403; UBA_AID_AAPK1; 1.
DR InterPro; IPR032270; AMPK_C.
DR InterPro; IPR039137; AMPKA1_C.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR028797; PRKAA1_UBA.
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..554
FT /note="5'-AMP-activated protein kinase catalytic subunit
FT alpha-1"
FT /id="PRO_0000085592"
FT DOMAIN 22..274
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 297..376
FT /note="AIS"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT REGION 480..531
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 145
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 28..36
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 51
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 27
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 178
FT /note="Phosphothreonine; by LKB1 and CaMKK2"
FT /evidence="ECO:0000250|UniProtKB:Q5EG47"
FT MOD_RES 264
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 350
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 351
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 355
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 363
FT /note="Phosphothreonine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 377
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 392
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 462
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 481
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 483
FT /note="Phosphothreonine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 485
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 491
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 503
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 519
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 522
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT NON_TER 1
SQ SEQUENCE 554 AA; 63393 MW; D33AA742EA2FAEE7 CRC64;
SWRKMATAEK QKHDGRVRIG HYILGDTLGV GTFGKVKVGK HELTGHKVAV KILNRQKIRS
LDVVGKIRRE IQNLKLFRHP HIIKLYQVIS TPSDIFMVME YVSGGELFDY ICKNGRLDEK
ESRRLFQQIL SGVDYCHRHM VVHRDLKPEN VLLDAHMNAK IADFGLSNMM SDGEFLRTSC
GSPNYAAPEV ISGRLYAGPE VDIWSSGVIL YALLCGTLPF DDDHVPTLFK KICDGIFYTP
QYLNPSVISL LKHMLQVDPM KRATIKDIRE HEWFKQDLPK YLFPEDPSYS STMIDDEALK
EVCEKFECSE EEVLSCLYNR NHQDPLAVAY HLIIDNRRIM NEAKDFYLAT SPPDSFLDDH
HLTRPHPERV PFLVAETPRA RHTLDELNPQ KSKHQGVRKA KWHLGIRSQS RPNDIMAEVC
RAIKQLDYEW KVVNPYYLRV RRKNPVTSTY SKMSLQLYQV DSRTYLLDFR SIDDEITEAK
SGTATPQRSG SVSNYRSCQR SDSDAEAQGK SSEVSLTSSV TSLDSSPVDL TPRPGSHTIE
FFEMCANLIK ILAQ
