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 gluc (updated: March 4, 2015)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

Total structural coverage: 100%

Model score: 85

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Variant	Description
	dbSNP:rs17855679
	a breast cancer sample

Biological Process

Activation of MAPK activity

Autophagy

Bile acid and bile salt transport

Bile acid signaling pathway

CAMKK-AMPK signaling cascade

Cell cycle arrest

Cellular response to calcium ion

Cellular response to drug

Cellular response to ethanol

Cellular response to glucose starvation

Cellular response to glucose stimulus

Cellular response to hydrogen peroxide

Cellular response to hypoxia

Cellular response to nutrient levels

Cellular response to organonitrogen compound

Cellular response to oxidative stress

Cellular response to prostaglandin E stimulus

Cholesterol biosynthetic process

Cold acclimation

Energy homeostasis

Fatty acid biosynthetic process

Fatty acid homeostasis

Fatty acid oxidation

Glucose homeostasis

Glucose metabolic process

Insulin receptor signaling pathway

Intracellular signal transduction

Lipid biosynthetic process

Macroautophagy

Motor behavior

Negative regulation of apoptotic process

Negative regulation of gene expression

Negative regulation of glucose import in response to insulin stimulus

Negative regulation of glucosylceramide biosynthetic process

Negative regulation of insulin receptor signaling pathway

Negative regulation of lipid catabolic process

Negative regulation of TOR signaling

Negative regulation of tubulin deacetylation

Neuron cellular homeostasis

Positive regulation of autophagy

Positive regulation of cell population proliferation

Positive regulation of cellular protein localization

Positive regulation of cholesterol biosynthetic process

Positive regulation of gene expression

Positive regulation of glycolytic process

Positive regulation of mitochondrial transcription

Positive regulation of peptidyl-lysine acetylation

Positive regulation of protein targeting to mitochondrion

Positive regulation of skeletal muscle tissue development

Protein heterooligomerization

Protein phosphorylation

Regulation of bile acid secretion

Regulation of circadian rhythm

Regulation of energy homeostasis

Regulation of macroautophagy

Regulation of microtubule cytoskeleton organization

Regulation of peptidyl-serine phosphorylation

Regulation of signal transduction by p53 class mediator

Regulation of stress granule assembly

Regulation of transcription, DNA-templated

Regulation of vesicle-mediated transport

Response to 17alpha-ethynylestradiol

Response to activity

Response to caffeine

Response to camptothecin

Response to gamma radiation

Response to hypoxia

Response to UV

Rhythmic process

Signal transduction

Transcription, DNA-templated

Wnt signaling pathway

Cellular Component

Apical plasma membrane

Axon

Cytoplasm

Cytosol

Dendrite

Intracellular anatomical structure

Neuronal cell body

Nuclear speck

Nucleoplasm

Nucleotide-activated protein kinase complex

Nucleus

Obsolete cell

Molecular Function

AMP-activated protein kinase activity

ATP binding

CAMP-dependent protein kinase activity

Chromatin binding

Histone serine kinase activity

Metal ion binding

Protein C-terminus binding

Protein kinase activity

Protein serine kinase activity

Protein serine/threonine kinase activity

Protein threonine kinase activity

Protein-containing complex binding

Tau protein binding

Tau-protein kinase activity

[acetyl-CoA carboxylase] kinase activity

[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity

The reference OMIM entry for this protein is 602739

Protein kinase, amp-activated, catalytic, alpha-1; prkaa1
Amp-activated protein kinase, catalytic, alpha-1
Ampk-alpha-1

DESCRIPTION

The mammalian 5-prime-AMP-activated protein kinase (AMPK) appears to play a role in protecting cells from stresses that cause ATP depletion by switching off ATP-consuming biosynthetic pathways. AMPK is a heterotrimeric protein composed of 1 alpha subunit (e.g., PRKAA1), 1 beta subunit (e.g., PRKAB1; 602740), and 1 gamma subunit (e.g., PRKAG1; 602742). The catalytic alpha subunit requires phosphorylation for full activity. It is related to the S. cerevisiae Snf1 protein kinase, which is involved in the response to nutritional stress. The noncatalytic beta and gamma subunits are related to yeast proteins that interact with Snf1: the beta subunit to the Sip1/Sip2/Gal83 family of transcription regulators, and the gamma subunit to Snf4, which is thought to be an activator of Snf1 (summary by Stapleton et al., 1996).

CLONING

Stapleton et al. (1996) reported the sequences of partial human liver cDNAs encoding AMPK-alpha-1. Stapleton et al. (1996) cloned rat hypothalamus cDNAs encoding Ampk-alpha-1. By Northern blot analysis, they detected low levels of a 6-kb Ampk-alpha-1 mRNA in all rat tissues examined except testis, where a low level of a 2.4-kb transcript was observed. The predicted 548-amino acid protein has a molecular mass of approximately 63 kD by SDS-PAGE. Rat Ampk-alpha-1 and Ampk-alpha-2 (600497) have 90% amino acid sequence identity within their catalytic cores but only 61% in their C-terminal tails.

MAPPING

By fluorescence in situ hybridization, Stapleton et al. (1997) mapped the human AMPK-alpha-1 gene to chromosome 5p12.

GENE FUNCTION

Adiponectin (605441) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. Yamauchi et al. (2002) demonstrated that phosphorylation and activation of AMPK are stimulated with globular and full-length adiponectin in skeletal muscle and only with full-length adiponectin in the liver. In parallel with its activation of AMPK, adiponectin stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC1; 200350), fatty acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by a dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty acid oxidation by adiponectin occurs through activation of AMPK. Yamauchi et al. (2002) concluded that their data provided a novel paradigm, that an adipocyte-derived antidiabetic hormone, adiponectin, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo. Minokoshi et al. (2004) investigated the potential role of AMP-activated protein kinase (AMPK) in the hypothalamus in the regulation of food intake. Minokoshi et al. (2004) reported that AMPK activity is inhibited in arcuate and paraventricular hypothalamus by the anorexigenic hormone leptin (164160), and in multiple hypothalamic regions by insulin (176730), high glucose, and refeeding. A melanocortin receptor (see 155555) agonist, a potent anorexigen, decreased AMPK activity in paraventricular hypothalamus, whereas agouti-related protein (602311), an orexigen, increased AMPK activity. Melanocortin receptor signaling is required for leptin and refeeding effects of AMPK in the paraventricular hypothalamus. Dominant-negative AMPK expression ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

June 20, 2017: Protein entry updated
Automatic update: comparative model was added.

March 15, 2016: Protein entry updated
Automatic update: OMIM entry 602739 was added.

5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1)