Alternative titles; symbols
HGNC Approved Gene Symbol: PRKAB1
Cytogenetic location: 12q24.23 Genomic coordinates (GRCh38) : 12:119,667,952-119,681,619 (from NCBI)
AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is activated by various cellular stresses that increase AMP levels and decrease ATP levels. Once activated, AMPK switches on catabolic pathways and switches off many ATP-consuming processes. AMPK is a heterotrimeric complex consisting of a catalytic alpha subunit (e.g., PRKAA1; 602739), a noncatalytic beta subunit (e.g., PRKAB1), and a noncatalytic gamma subunit (e.g., PRKAG1; 602742). AMPK beta subunits function as scaffolds for complex assembly and also determine the subcellular localization and substrate specificity of the complex. AMPK is evolutionarily conserved, and orthologs for all 3 subunits are found throughout eukaryotes (review by Sanz, 2008).
Using PCR with degenerate oligonucleotides based on the rat Ampk-beta-1 protein sequence, Woods et al. (1996) isolated rat liver cDNAs encoding Ampk-beta-1. Both the Ampk-beta-1 mRNA and protein are widely expressed in rat tissues. The predicted 270-amino acid protein has a calculated mass of 30 kD, but Woods et al. (1996) reported that it migrates as a 38-kD protein by SDS-PAGE. Immunoprecipitation studies suggested that Ampk-beta-1 mediates the association of the AMPK heterotrimeric complex in vitro.
By searching the sequence databases with a rat Ampk-beta-1 cDNA, Stapleton et al. (1997) identified an EST encoding human AMPK-beta-1. The human and rat AMPK-beta-1 proteins have 95% amino acid sequence identity. Thornton et al. (1998) reported that the predicted 271-amino acid human AMPK-beta-1 protein shares 71% sequence identity with human AMPK-beta-2 (PRKAB2; 602741). They found that both beta isoforms form complexes with Ampk-alpha-1 (PRKAA1) and Ampk-alpha-2 (PRKAA2; 600497) in rat liver and skeletal muscle. Coexpression of the alpha and AMPK-gamma-1 (PRKAG1; 602742) subunits with either AMPK-beta-1 or AMPK-beta-2 in mammalian cells did not reveal a significant difference in AMPK activity between the 2 beta isoforms. Using Western blot analysis and immunoprecipitation studies, Thornton et al. (1998) determined that Ampk-beta-1 was expressed at higher levels than Ampk-beta-2 in rat liver, while Ampk-beta-2 was more abundant in skeletal muscle. They suggested that the marked difference in expression patterns of Ampk-beta-1 and Ampk-beta-2 indicates tissue-specific roles for these isoforms. By Northern blot analysis, Thornton et al. (1998) found that AMPK-beta-1 was expressed as a 3-kb mRNA in all tissues tested.
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 in the hypothalamus was sufficient to reduce food intake and body weight, whereas constitutively active AMPK increased both. Alterations of hypothalamic AMPK activity augmented changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, Minokoshi et al. (2004) concluded that hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
Baba et al. (2006) showed that FNIP1 (610594) interacted with the alpha, beta, and gamma subunits of AMPK. FNIP1 was phosphorylated by AMPK, and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN (607273) phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR (FRAP1; 601231) and AMPK signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.
Stapleton et al. (1997) mapped the human AMPK-beta-1 gene to 12q24.1 by fluorescence in situ hybridization.
Crystal Structure
Xiao et al. (2007) reported the crystal structure of the regulatory fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate groups of AMP/ATP lie in a groove on the surface of the gamma domain, which is lined with basic residues, many of which are associated with disease-causing mutations. Structural and solution studies revealed that 2 sites on the gamma domain bind either AMP or magnesium ATP, whereas a third site contains a tightly bound AMP that does not exchange. Xiao et al. (2007) stated that their binding studies indicated that under physiologic conditions AMPK mainly exists in its inactive form in complex with magnesium ATP, which is much more abundant than AMP. Their modeling studies suggested how changes in the concentration of AMP enhance AMPK activity levels. The structure also suggested a mechanism for propagating AMP/ATP signaling whereby a phosphorylated residue from the alpha and/or beta subunits binds to the gamma subunit in the presence of AMP but not when ATP is bound.
Baba, M., Hong, S.-B., Sharma, N., Warren, M. B., Nickerson, M. L., Iwamatsu, A., Esposito, D., Gillette, W. K., Hopkins, R. F., III, Hartley, J. L., Furihata, M., Oishi, S., Zhen, W., Burke, T. R., Jr., Linehan, W. M., Schmidt, L. S., Zbar, B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc. Nat. Acad. Sci. 103: 15552-15557, 2006. [PubMed: 17028174] [Full Text: https://doi.org/10.1073/pnas.0603781103]
Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.-B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferre, P., Birnbaum, M. J., Stuck, B. J., Kahn, B. B. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569-574, 2004. [PubMed: 15058305] [Full Text: https://doi.org/10.1038/nature02440]
Sanz, P. AMP-activated protein kinase: structure and regulation. Curr. Protein Pept. Sci. 9: 478-492, 2008. [PubMed: 18855699] [Full Text: https://doi.org/10.2174/138920308785915254]
Stapleton, D., Woollatt, E., Mitchelhill, K. I., Nicholl, J. K., Fernandez, C. S., Michell, B. J., Witters, L. A., Power, D. A., Sutherland, G. R., Kemp, B. E. AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location. FEBS Lett. 409: 452-456, 1997. [PubMed: 9224708] [Full Text: https://doi.org/10.1016/s0014-5793(97)00569-3]
Thornton, C., Snowden, M. A., Carling, D. Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle. J. Biol. Chem. 273: 12443-12450, 1998. [PubMed: 9575201] [Full Text: https://doi.org/10.1074/jbc.273.20.12443]
Woods, A., Cheung, P. C. F., Smith, F. C., Davison, M. D., Scott, J., Beri, R. K., Carling, D. Characterization of AMP-activated protein kinase beta and gamma subunits: assembly of the heterotrimeric complex in vitro. J. Biol. Chem. 271: 10282-10290, 1996. [PubMed: 8626596] [Full Text: https://doi.org/10.1074/jbc.271.17.10282]
Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T., Martin, S. R., Carling, D., Gamblin, S. J. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449: 496-500, 2007. [PubMed: 17851531] [Full Text: https://doi.org/10.1038/nature06161]