Names & Taxonomy
- Uniprot ID:
- P54646
- Entry Name:
- AAPK2_HUMAN
- Status:
- reviewed
- Protein Names:
- 5'-AMP-activated protein kinase catalytic subunit alpha-2 (AMPK subunit alpha-2) (EC 2.7.11.1) (Acetyl-CoA carboxylase kinase) (ACACA kinase) (EC 2.7.11.27) (Hydroxymethylglutaryl-CoA reductase kinase) (HMGCR kinase) (EC 2.7.11.31)
- Gene Names:
- PRKAA2 AMPK AMPK2
- Gene Names Primary:
- PRKAA2
- Organism:
- Homo sapiens (Human)
Structure
- Length:
- 552
- Sequence:
- MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLFQQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVYRAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQRSGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFFEMCASLITTLAR
- Proteomes:
- UP000005640
Subcellular location
- Subcellular Location:
- Cytoplasm
Function
- 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. Involved in insulin receptor/INSR internalization (PubMed:25687571). 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).
- Catalytic Activity:
- ATP + a protein = ADP + a phosphoprotein.
- Cofactor:
- COFACTOR: Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
- Enzyme Regulation:
- ENZYME REGULATION: 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. 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--3-pyridin-4-yl-pyyrazolo 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.
- Active Site:
- ACT_SITE 139 139 Proton acceptor.
- Cross Reference Drug Bank:
- DB00945
- Gene Ontology Go:
- cytoplasm
cytosol
nucleoplasm
nucleotide-activated protein kinase complex
kinase activity
kinase activity
AMP-activated protein kinase activity
ATP binding
chromatin binding
histone serine kinase activity
metal ion binding
protein kinase activity
protein serine/threonine kinase activity
protein serine/threonine/tyrosine kinase activity
carnitine shuttle
cell cycle arrest
cellular lipid metabolic process
cellular response to drug
cellular response to glucose starvation
cellular response to nutrient levels
cellular response to prostaglandin E stimulus
cholesterol biosynthetic process
energy reserve metabolic process
fatty acid biosynthetic process
fatty acid homeostasis
gene expression
glucose homeostasis
histone-serine phosphorylation
insulin receptor signaling pathway
intracellular signal transduction
lipid biosynthetic process
macroautophagy
membrane organization
mitochondrion organization
negative regulation of apoptotic process
negative regulation of TOR signaling
organelle organization
positive regulation of autophagy
positive regulation of glycolytic process
positive regulation of macroautophagy
protein phosphorylation
regulation of circadian rhythm
regulation of energy homeostasis
regulation of fatty acid biosynthetic process
regulation of macroautophagy
regulation of transcription, DNA-templated
response to muscle activity
response to stress
rhythmic process
signal transduction
small molecule metabolic process
transcription initiation from RNA polymerase II promoter
Wnt signaling pathway - Gene Ontology Biological Process:
- carnitine shuttle
cell cycle arrest
cellular lipid metabolic process
cellular response to drug
cellular response to glucose starvation
cellular response to nutrient levels
cellular response to prostaglandin E stimulus
cholesterol biosynthetic process
energy reserve metabolic process
fatty acid biosynthetic process
fatty acid homeostasis
gene expression
glucose homeostasis
histone-serine phosphorylation
insulin receptor signaling pathway
intracellular signal transduction
lipid biosynthetic process
macroautophagy
membrane organization
mitochondrion organization
negative regulation of apoptotic process
negative regulation of TOR signaling
organelle organization
positive regulation of autophagy
positive regulation of glycolytic process
positive regulation of macroautophagy
protein phosphorylation
regulation of circadian rhythm
regulation of energy homeostasis
regulation of fatty acid biosynthetic process
regulation of macroautophagy
regulation of transcription, DNA-templated
response to muscle activity
response to stress
rhythmic process
signal transduction
small molecule metabolic process
transcription initiation from RNA polymerase II promoter
Wnt signaling pathway - Gene Ontology Molecular Function:
- kinase activity
kinase activity
AMP-activated protein kinase activity
ATP binding
chromatin binding
histone serine kinase activity
metal ion binding
protein kinase activity
protein serine/threonine/tyrosine kinase activity
protein serine/threonine kinase activity - Gene Ontology Cellular Component:
- cytoplasm
cytosol
nucleoplasm
nucleotide-activated protein kinase complex - Keywords:
- 3D-structure
ATP-binding
Autophagy
Biological rhythms
Cholesterol biosynthesis
Cholesterol metabolism
Chromatin regulator
Complete proteome
Cytoplasm
Fatty acid biosynthesis
Fatty acid metabolism
Kinase
Lipid biosynthesis
Lipid metabolism
Magnesium
Metal-binding
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Reference proteome
Serine/threonine-protein kinase
Steroid biosynthesis
Steroid metabolism
Sterol biosynthesis
Sterol metabolism
Transcription
Transcription regulation
Transferase
Ubl conjugation
Wnt signaling pathway - Interacts With:
- Q9NYB9; Q08117; Q13155; Q92624; Q9NPC3; Q6FG41; P08151; Q6NT76; Q8IX15-3; Q719H9; Q5T7B8-2; Q9BVG8; Q15323; Q96JM7; H3BTW2; Q15233-2; Q7Z3S9; Q86Y26; O43741; P54619; Q93062; Q8HWS3; P15884; Q15654; Q9Y3Q8; Q8N6Y0; Q8N1B4; Q96BR9; Q8NF99