ID:AAPK1_HUMAN DESCRIPTION: RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-1; Short=AMPK subunit alpha-1; EC=2.7.11.1; AltName: Full=Acetyl-CoA carboxylase kinase; Short=ACACA kinase; EC=2.7.11.27; AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase; Short=HMGCR kinase; EC=2.7.11.31; AltName: Full=Tau-protein kinase PRKAA1; EC=2.7.11.26; FUNCTION: 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. 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: 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 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 has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CATALYTIC ACTIVITY: ATP + [tau protein] = ADP + [tau protein] phosphate. CATALYTIC ACTIVITY: ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate. CATALYTIC ACTIVITY: ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate. COFACTOR: Magnesium. ENZYME REGULATION: Activated by phosphorylation on Thr-183. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-183. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-183. ADP also stimulates Thr- 183 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-183, 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. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). 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. SUBUNIT: 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. INTERACTION: O43741:PRKAB2; NbExp=5; IntAct=EBI-1181405, EBI-1053424; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=In response to stress, recruited by p53/TP53 to specific promoters. DOMAIN: The AIS (autoinhibitory sequence) region some sequence similarity with the ubiquitin-associated domains and represses kinase activity. PTM: Ubiquitinated (By similarity). PTM: Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-183 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-183, but at a much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK. SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=AAA64850.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=AAD43027.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=AAH37303.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=BAA36547.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=BAG35788.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF07714 - Protein tyrosine and serine/threonine kinase PF16579 - Adenylate sensor of SNF1-like protein kinase
SCOP Domains: 103243 - KA1-like 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on Q13131
Front
Top
Side
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.
Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000166 nucleotide binding GO:0003682 chromatin binding GO:0004672 protein kinase activity GO:0004674 protein serine/threonine kinase activity GO:0004679 AMP-activated protein kinase activity GO:0004691 cAMP-dependent protein kinase activity GO:0005515 protein binding GO:0005524 ATP binding GO:0008022 protein C-terminus binding GO:0016301 kinase activity GO:0016740 transferase activity GO:0035174 histone serine kinase activity GO:0046872 metal ion binding GO:0047322 [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity GO:0050321 tau-protein kinase activity GO:0050405 [acetyl-CoA carboxylase] kinase activity
Biological Process: GO:0000187 activation of MAPK activity GO:0001666 response to hypoxia GO:0006006 glucose metabolic process GO:0006325 chromatin organization GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006468 protein phosphorylation GO:0006629 lipid metabolic process GO:0006631 fatty acid metabolic process GO:0006633 fatty acid biosynthetic process GO:0006694 steroid biosynthetic process GO:0006695 cholesterol biosynthetic process GO:0006914 autophagy GO:0007050 cell cycle arrest GO:0007165 signal transduction GO:0008202 steroid metabolic process GO:0008203 cholesterol metabolic process GO:0008284 positive regulation of cell proliferation GO:0008610 lipid biosynthetic process GO:0009411 response to UV GO:0009631 cold acclimation GO:0010332 response to gamma radiation GO:0010508 positive regulation of autophagy GO:0010628 positive regulation of gene expression GO:0010629 negative regulation of gene expression GO:0014823 response to activity GO:0016055 Wnt signaling pathway GO:0016126 sterol biosynthetic process GO:0016236 macroautophagy GO:0016310 phosphorylation GO:0019395 fatty acid oxidation GO:0031000 response to caffeine GO:0031669 cellular response to nutrient levels GO:0032007 negative regulation of TOR signaling GO:0033135 regulation of peptidyl-serine phosphorylation GO:0034599 cellular response to oxidative stress GO:0035404 histone-serine phosphorylation GO:0042149 cellular response to glucose starvation GO:0042542 response to hydrogen peroxide GO:0042593 glucose homeostasis GO:0042752 regulation of circadian rhythm GO:0043066 negative regulation of apoptotic process GO:0045542 positive regulation of cholesterol biosynthetic process GO:0045821 positive regulation of glycolytic process GO:0046318 negative regulation of glucosylceramide biosynthetic process GO:0048511 rhythmic process GO:0048643 positive regulation of skeletal muscle tissue development GO:0050995 negative regulation of lipid catabolic process GO:0051291 protein heterooligomerization GO:0055089 fatty acid homeostasis GO:0060627 regulation of vesicle-mediated transport GO:0061762 CAMKK-AMPK signaling cascade GO:0070301 cellular response to hydrogen peroxide GO:0070507 regulation of microtubule cytoskeleton organization GO:0071277 cellular response to calcium ion GO:0071333 cellular response to glucose stimulus GO:0071361 cellular response to ethanol GO:0071380 cellular response to prostaglandin E stimulus GO:0071417 cellular response to organonitrogen compound GO:0071456 cellular response to hypoxia GO:0097009 energy homeostasis GO:1901563 response to camptothecin GO:1903109 positive regulation of transcription from mitochondrial promoter GO:1903829 positive regulation of cellular protein localization GO:1903955 positive regulation of protein targeting to mitochondrion GO:1904428 negative regulation of tubulin deacetylation GO:2000758 positive regulation of peptidyl-lysine acetylation GO:2001274 negative regulation of glucose import in response to insulin stimulus
BioCarta from NCI Cancer Genome Anatomy Project h_chrebpPathway - ChREBP regulation by carbohydrates and cAMP h_leptinPathway - Reversal of Insulin Resistance by Leptin
Reactome (by CSHL, EBI, and GO)
Protein Q13131 (Reactome details) participates in the following event(s):
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
