Q09136 (AAPK1_PIG) Reviewed, UniProtKB/Swiss-Prot
Last modified June 11, 2014. Version 98. History...
Names and origin
|Protein names||Recommended name:|
5'-AMP-activated protein kinase catalytic subunit alpha-1
Short name=AMPK subunit alpha-1
|Organism||Sus scrofa (Pig) [Reference proteome]|
|Taxonomic identifier||9823 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Suina › Suidae › Sus|
|Sequence length||385 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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/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 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 By similarity. Ref.1
ATP + a protein = ADP + a phosphoprotein.
ATP + [tau protein] = ADP + [tau protein] phosphate.
ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate.
ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate.
Magnesium By similarity.
Activated by phosphorylation on Thr-133. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-133. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-133. ADP also stimulates Thr-133 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-133, 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. 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 By similarity.
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.
The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity By similarity.
Ubiquitinated By similarity.
Phosphorylated at Thr-133 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-133 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-133, 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 By similarity. Dephosphorylated by PPM1A and PPM1B By similarity.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||‹1 – ›385||›385||5'-AMP-activated protein kinase catalytic subunit alpha-1||PRO_0000085591|
|Domain||‹1 – 229||›229||Protein kinase|
|Nucleotide binding||15 – ›22||›8||ATP By similarity|
|Region||252 – 297||46||AIS By similarity|
|Active site||100||1||Proton acceptor By similarity|
Amino acid modifications
|Modified residue||14||1||Phosphothreonine By similarity|
|Modified residue||133||1||Phosphothreonine; by LKB1 and CaMKK2 By similarity|
|Modified residue||219||1||Phosphothreonine By similarity|
|Modified residue||277||1||Phosphoserine By similarity|
|Modified residue||281||1||Phosphoserine; by ULK1 By similarity|
|Modified residue||289||1||Phosphothreonine; by ULK1 By similarity|
|Modified residue||298||1||Phosphothreonine By similarity|
|Modified residue||353||1||Phosphoserine By similarity|
|Non-adjacent residues||22 – 23||2|
|Non-adjacent residues||157 – 158||2|
|Non-adjacent residues||255 – 256||2|
|Non-adjacent residues||270 – 271||2|
|Non-adjacent residues||290 – 291||2|
|Non-adjacent residues||300 – 301||2|
|Non-adjacent residues||323 – 324||2|
|Non-adjacent residues||342 – 343||2|
|Non-adjacent residues||367 – 368||2|
|||"Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase."|
Mitchelhill K.I., Stapleton D., Gao G., House C., Michell B., Katsis F., Witters L.A., Kemp B.E.
J. Biol. Chem. 269:2361-2364(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 1-22; 73-87; 100-157; 222-240 AND 344-361, FUNCTION.
|||"Mammalian AMP-activated protein kinase subfamily."|
Stapleton D., Mitchelhill K.I., Gao G., Widmer J., Michell B.J., Teh T., House C.M., Fernandez C.S., Cox T., Witters L.A., Kemp B.E.
J. Biol. Chem. 271:611-614(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 1-22; 73-88; 100-132; 144-156; 209-216; 221-255; 256-270; 271-290; 291-300; 301-323; 324-342; 343-367 AND 368-385.
|||"Effect of dietary hemicellulose on growth and energy metabolism of growing pigs."|
Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 23-243.
|EU622639 mRNA. Translation: ACC78144.1.|
3D structure databases
Protocols and materials databases
Family and domain databases
|InterPro||IPR028375. KA1/Ssp2_C. |
|PANTHER||PTHR24343:SF81. PTHR24343:SF81. 1 hit. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF103243. SSF103243. 1 hit. |
SSF56112. SSF56112. 1 hit.
|PROSITE||PS50011. PROTEIN_KINASE_DOM. 1 hit. |
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: Q09136|
Secondary accession number(s): B2MV24
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families