AAPK1_MOUSE
ID AAPK1_MOUSE Reviewed; 559 AA.
AC Q5EG47;
DT 13-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 28-JUL-2009, sequence version 2.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-1;
DE Short=AMPK subunit alpha-1;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:P54645};
DE AltName: Full=Acetyl-CoA carboxylase kinase;
DE Short=ACACA kinase;
DE EC=2.7.11.27 {ECO:0000250|UniProtKB:P54645};
DE AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase;
DE Short=HMGCR kinase;
DE EC=2.7.11.31 {ECO:0000250|UniProtKB:P54645};
DE AltName: Full=Tau-protein kinase PRKAA1;
DE EC=2.7.11.26 {ECO:0000250|UniProtKB:P54645};
GN Name=Prkaa1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 10-559.
RC STRAIN=C57BL/6N; TISSUE=Muscle;
RA Xie X., Chen Y.;
RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP ACTIVITY REGULATION, AND PHOSPHORYLATION AT THR-183.
RX PubMed=16054095; DOI=10.1016/j.cmet.2005.05.009;
RA Hawley S.A., Pan D.A., Mustard K.J., Ross L., Bain J., Edelman A.M.,
RA Frenguelli B.G., Hardie D.G.;
RT "Calmodulin-dependent protein kinase kinase-beta is an alternative upstream
RT kinase for AMP-activated protein kinase.";
RL Cell Metab. 2:9-19(2005).
RN [4]
RP FUNCTION IN PHOSPHORYLATION OF LIPE, AND MUTAGENESIS OF ASP-168.
RX PubMed=15878856; DOI=10.1074/jbc.m414222200;
RA Daval M., Diot-Dupuy F., Bazin R., Hainault I., Viollet B., Vaulont S.,
RA Hajduch E., Ferre P., Foufelle F.;
RT "Anti-lipolytic action of AMP-activated protein kinase in rodent
RT adipocytes.";
RL J. Biol. Chem. 280:25250-25257(2005).
RN [5]
RP PHOSPHORYLATION AT THR-183, AND ACTIVITY REGULATION.
RX PubMed=15980064; DOI=10.1074/jbc.m503824200;
RA Hurley R.L., Anderson K.A., Franzone J.M., Kemp B.E., Means A.R.,
RA Witters L.A.;
RT "The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated
RT protein kinase kinases.";
RL J. Biol. Chem. 280:29060-29066(2005).
RN [6]
RP FUNCTION IN PHOSPHORYLATION OF CRTC2.
RX PubMed=16148943; DOI=10.1038/nature03967;
RA Koo S.-H., Flechner L., Qi L., Zhang X., Screaton R.A., Jeffries S.,
RA Hedrick S., Xu W., Boussouar F., Brindle P., Takemori H., Montminy M.;
RT "The CREB coactivator TORC2 is a key regulator of fasting glucose
RT metabolism.";
RL Nature 437:1109-1111(2005).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF CRTC2, AND PHOSPHORYLATION AT THR-183.
RX PubMed=16308421; DOI=10.1126/science.1120781;
RA Shaw R.J., Lamia K.A., Vasquez D., Koo S.-H., Bardeesy N., Depinho R.A.,
RA Montminy M., Cantley L.C.;
RT "The kinase LKB1 mediates glucose homeostasis in liver and therapeutic
RT effects of metformin.";
RL Science 310:1642-1646(2005).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF TBC1D4.
RX PubMed=16804075; DOI=10.2337/db06-0175;
RA Treebak J.T., Glund S., Deshmukh A., Klein D.K., Long Y.C., Jensen T.E.,
RA Jorgensen S.B., Viollet B., Andersson L., Neumann D., Wallimann T.,
RA Richter E.A., Chibalin A.V., Zierath J.R., Wojtaszewski J.F.;
RT "AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on
RT AMPK catalytic and regulatory subunits.";
RL Diabetes 55:2051-2058(2006).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF TBC1D4.
RX PubMed=16804077; DOI=10.2337/db06-0150;
RA Kramer H.F., Witczak C.A., Fujii N., Jessen N., Taylor E.B., Arnolds D.E.,
RA Sakamoto K., Hirshman M.F., Goodyear L.J.;
RT "Distinct signals regulate AS160 phosphorylation in response to insulin,
RT AICAR, and contraction in mouse skeletal muscle.";
RL Diabetes 55:2067-2076(2006).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [11]
RP UBIQUITINATION.
RX PubMed=18254724; DOI=10.1042/bj20080067;
RA Al-Hakim A.K., Zagorska A., Chapman L., Deak M., Peggie M., Alessi D.R.;
RT "Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-
RT linked polyubiquitin chains.";
RL Biochem. J. 411:249-260(2008).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF RPTOR.
RX PubMed=18439900; DOI=10.1016/j.molcel.2008.03.003;
RA Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A.,
RA Vasquez D.S., Turk B.E., Shaw R.J.;
RT "AMPK phosphorylation of raptor mediates a metabolic checkpoint.";
RL Mol. Cell 30:214-226(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-496, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [14]
RP FUNCTION IN PHOSPHORYLATION OF CRY1, AND SUBCELLULAR LOCATION.
RX PubMed=19833968; DOI=10.1126/science.1172156;
RA Lamia K.A., Sachdeva U.M., DiTacchio L., Williams E.C., Alvarez J.G.,
RA Egan D.F., Vasquez D.S., Juguilon H., Panda S., Shaw R.J., Thompson C.B.,
RA Evans R.M.;
RT "AMPK regulates the circadian clock by cryptochrome phosphorylation and
RT degradation.";
RL Science 326:437-440(2009).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF CTNNB1.
RX PubMed=20361929; DOI=10.1016/j.bbrc.2010.03.161;
RA Zhao J., Yue W., Zhu M.J., Sreejayan N., Du M.;
RT "AMP-activated protein kinase (AMPK) cross-talks with canonical Wnt
RT signaling via phosphorylation of beta-catenin at Ser 552.";
RL Biochem. Biophys. Res. Commun. 395:146-151(2010).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-486 AND THR-490, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Lung, Pancreas, Spleen, and
RC Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [17]
RP FUNCTION IN PHOSPHORYLATION OF H2B.
RX PubMed=20647423; DOI=10.1126/science.1191241;
RA Bungard D., Fuerth B.J., Zeng P.Y., Faubert B., Maas N.L., Viollet B.,
RA Carling D., Thompson C.B., Jones R.G., Berger S.L.;
RT "Signaling kinase AMPK activates stress-promoted transcription via histone
RT H2B phosphorylation.";
RL Science 329:1201-1205(2010).
RN [18]
RP PHOSPHORYLATION BY ULK1 AND ULK2.
RX PubMed=21460634; DOI=10.4161/auto.7.7.15451;
RA Loffler A.S., Alers S., Dieterle A.M., Keppeler H., Franz-Wachtel M.,
RA Kundu M., Campbell D.G., Wesselborg S., Alessi D.R., Stork B.;
RT "Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory
RT feedback loop.";
RL Autophagy 7:696-706(2011).
RN [19]
RP FUNCTION IN PHOSPHORYLATION OF SREBF1 AND SREBF2, AND ACTIVITY REGULATION.
RX PubMed=21459323; DOI=10.1016/j.cmet.2011.03.009;
RA Li Y., Xu S., Mihaylova M.M., Zheng B., Hou X., Jiang B., Park O., Luo Z.,
RA Lefai E., Shyy J.Y., Gao B., Wierzbicki M., Verbeuren T.J., Shaw R.J.,
RA Cohen R.A., Zang M.;
RT "AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic
RT steatosis and atherosclerosis in diet-induced insulin-resistant mice.";
RL Cell Metab. 13:376-388(2011).
RN [20]
RP FUNCTION IN PHOSPHORYLATION OF ULK1, AND MUTAGENESIS OF ASP-168.
RX PubMed=21258367; DOI=10.1038/ncb2152;
RA Kim J., Kundu M., Viollet B., Guan K.L.;
RT "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.";
RL Nat. Cell Biol. 13:132-141(2011).
RN [21]
RP FUNCTION IN PHOSPHORYLATION OF ULK1.
RX PubMed=21205641; DOI=10.1126/science.1196371;
RA Egan D.F., Shackelford D.B., Mihaylova M.M., Gelino S., Kohnz R.A.,
RA Mair W., Vasquez D.S., Joshi A., Gwinn D.M., Taylor R., Asara J.M.,
RA Fitzpatrick J., Dillin A., Viollet B., Kundu M., Hansen M., Shaw R.J.;
RT "Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects
RT energy sensing to mitophagy.";
RL Science 331:456-461(2011).
RN [22]
RP FUNCTION.
RX PubMed=23283301; DOI=10.1007/s00018-012-1244-6;
RA Peserico A., Chiacchiera F., Grossi V., Matrone A., Latorre D.,
RA Simonatto M., Fusella A., Ryall J.G., Finley L.W., Haigis M.C., Villani G.,
RA Puri P.L., Sartorelli V., Simone C.;
RT "A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing
RT glucose levels.";
RL Cell. Mol. Life Sci. 70:2015-2029(2013).
RN [23]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=34077757; DOI=10.1016/j.molcel.2021.05.005;
RA Liu R., Lee J.H., Li J., Yu R., Tan L., Xia Y., Zheng Y., Bian X.L.,
RA Lorenzi P.L., Chen Q., Lu Z.;
RT "Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of
RT lipid droplets.";
RL Mol. Cell 81:2722-2735(2021).
CC -!- FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an
CC energy sensor protein kinase that plays a key role in regulating
CC cellular energy metabolism (By similarity). In response to reduction of
CC intracellular ATP levels, AMPK activates energy-producing pathways and
CC inhibits energy-consuming processes: inhibits protein, carbohydrate and
CC lipid biosynthesis, as well as cell growth and proliferation (By
CC similarity). AMPK acts via direct phosphorylation of metabolic enzymes,
CC and by longer-term effects via phosphorylation of transcription
CC regulators (By similarity). Regulates lipid synthesis by
CC phosphorylating and inactivating lipid metabolic enzymes such as ACACA,
CC ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol
CC synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB)
CC and hormone-sensitive lipase (LIPE) enzymes, respectively
CC (PubMed:15878856). Promotes lipolysis of lipid droplets by mediating
CC phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757).
CC Regulates insulin-signaling and glycolysis by phosphorylating IRS1,
CC PFKFB2 and PFKFB3 (By similarity). AMPK stimulates glucose uptake in
CC muscle by increasing the translocation of the glucose transporter
CC SLC2A4/GLUT4 to the plasma membrane, possibly by mediating
CC phosphorylation of TBC1D4/AS160 (PubMed:16804075, PubMed:16804077).
CC Regulates transcription and chromatin structure by phosphorylating
CC transcription regulators involved in energy metabolism such as
CC CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300,
CC HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (PubMed:16148943,
CC PubMed:16308421, PubMed:20647423, PubMed:21459323). Acts as a key
CC regulator of glucose homeostasis in liver by phosphorylating
CC CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm
CC (PubMed:16148943, PubMed:16308421). In response to stress,
CC phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote
CC transcription (PubMed:20647423). Acts as a key regulator of cell growth
CC and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in
CC response to nutrient limitation, negatively regulates the mTORC1
CC complex by phosphorylating RPTOR component of the mTORC1 complex and by
CC phosphorylating and activating TSC2 (PubMed:18439900, PubMed:21258367,
CC PubMed:21205641). In response to nutrient limitation, promotes
CC autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21258367,
CC PubMed:21205641). In that process also activates WDR45/WIPI4 (By
CC similarity). Phosphorylates CASP6, thereby preventing its
CC autoprocessing and subsequent activation (By similarity). In response
CC to nutrient limitation, phosphorylates transcription factor FOXO3
CC promoting FOXO3 mitochondrial import (PubMed:23283301). Also acts as a
CC regulator of cellular polarity by remodeling the actin cytoskeleton;
CC probably by indirectly activating myosin (By similarity). AMPK also
CC acts as a regulator of circadian rhythm by mediating phosphorylation of
CC CRY1, leading to destabilize it (PubMed:19833968). May regulate the Wnt
CC signaling pathway by phosphorylating CTNNB1, leading to stabilize it
CC (PubMed:20361929). Also has tau-protein kinase activity: in response to
CC amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to
CC phosphorylation of MAPT/TAU; however the relevance of such data remains
CC unclear in vivo (By similarity). Also phosphorylates CFTR, EEF2K, KLC1,
CC NOS3 and SLC12A1 (By similarity). {ECO:0000250|UniProtKB:P54645,
CC ECO:0000250|UniProtKB:Q13131, ECO:0000269|PubMed:15878856,
CC ECO:0000269|PubMed:16148943, ECO:0000269|PubMed:16308421,
CC ECO:0000269|PubMed:16804075, ECO:0000269|PubMed:16804077,
CC ECO:0000269|PubMed:18439900, ECO:0000269|PubMed:19833968,
CC ECO:0000269|PubMed:20361929, ECO:0000269|PubMed:20647423,
CC ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:21258367,
CC ECO:0000269|PubMed:21459323, ECO:0000269|PubMed:23283301,
CC ECO:0000269|PubMed:34077757}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:34077757};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[acetyl-CoA carboxylase] = ADP + H(+) + O-
CC phospho-L-seryl-[acetyl-CoA carboxylase]; Xref=Rhea:RHEA:20333,
CC Rhea:RHEA-COMP:13722, Rhea:RHEA-COMP:13723, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421,
CC ChEBI:CHEBI:456216; EC=2.7.11.27;
CC Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A
CC reductase] = ADP + H(+) + O-phospho-L-seryl-[3-hydroxy-3-
CC methylglutaryl-coenzyme A reductase]; Xref=Rhea:RHEA:23172,
CC Rhea:RHEA-COMP:13692, Rhea:RHEA-COMP:13693, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421,
CC ChEBI:CHEBI:456216; EC=2.7.11.31;
CC Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[tau protein] = ADP + H(+) + O-phospho-L-seryl-
CC [tau protein]; Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-
CC COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26;
CC Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[tau protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[tau protein]; Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703,
CC Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.26; Evidence={ECO:0000250|UniProtKB:P54645};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-183. Binding
CC of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3)
CC results in allosteric activation, inducing phosphorylation on Thr-183.
CC AMP-binding to gamma subunit also sustains activity by preventing
CC dephosphorylation of Thr-183. ADP also stimulates Thr-183
CC phosphorylation, without stimulating already phosphorylated AMPK. ATP
CC promotes dephosphorylation of Thr-183, rendering the enzyme inactive.
CC Under physiological conditions AMPK mainly exists in its inactive form
CC in complex with ATP, which is much more abundant than AMP. Selectively
CC inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-
CC pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a
CC natural polyphenol present in red wine, and S17834, a synthetic
CC polyphenol. {ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:16054095,
CC ECO:0000269|PubMed:21459323}.
CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1
CC or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic
CC subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.
CC {ECO:0000250|UniProtKB:Q13131}.
CC -!- INTERACTION:
CC Q5EG47; P46937: YAP1; Xeno; NbExp=2; IntAct=EBI-7282395, EBI-1044059;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q13131}. Nucleus
CC {ECO:0000269|PubMed:19833968}. Note=In response to stress, recruited by
CC p53/TP53 to specific promoters. {ECO:0000250|UniProtKB:Q13131}.
CC -!- DOMAIN: The AIS (autoinhibitory sequence) region shows some sequence
CC similarity with the ubiquitin-associated domains and represses kinase
CC activity. {ECO:0000250|UniProtKB:Q13131}.
CC -!- PTM: Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39. Also
CC phosphorylated at Thr-183 by CAMKK2; triggered by a rise in
CC intracellular calcium ions, without detectable changes in the AMP/ATP
CC ratio. CAMKK1 can also phosphorylate Thr-183, but at a much lower
CC level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and
CC PP2C). Phosphorylated by ULK1 and ULK2; leading to negatively regulate
CC AMPK activity and suggesting the existence of a regulatory feedback
CC loop between ULK1, ULK2 and AMPK. Dephosphorylated by PPM1A and PPM1B
CC (By similarity). {ECO:0000250|UniProtKB:Q13131}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:18254724}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. SNF1 subfamily. {ECO:0000305}.
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DR EMBL; AC131919; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135079; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AY885266; AAW79567.1; -; mRNA.
DR CCDS; CCDS49574.1; -.
DR RefSeq; NP_001013385.3; NM_001013367.3.
DR PDB; 5UFU; X-ray; 3.45 A; A=11-480, A=536-559.
DR PDBsum; 5UFU; -.
DR AlphaFoldDB; Q5EG47; -.
DR SMR; Q5EG47; -.
DR BioGRID; 222923; 36.
DR ComplexPortal; CPX-5698; AMPK complex, alpha1-beta1-gamma1 variant.
DR ComplexPortal; CPX-5849; AMPK complex, alpha1-beta1-gamma2 variant.
DR ComplexPortal; CPX-5853; AMPK complex, alpha1-beta2-gamma1 variant.
DR ComplexPortal; CPX-5855; AMPK complex, alpha1-beta2-gamma3 variant.
DR ComplexPortal; CPX-5856; AMPK complex, alpha1-beta1-gamma3 variant.
DR ComplexPortal; CPX-5860; AMPK complex, alpha1-beta2-gamma2 variant.
DR CORUM; Q5EG47; -.
DR DIP; DIP-47622N; -.
DR IntAct; Q5EG47; 28.
DR MINT; Q5EG47; -.
DR STRING; 10090.ENSMUSP00000063166; -.
DR BindingDB; Q5EG47; -.
DR ChEMBL; CHEMBL1075161; -.
DR CarbonylDB; Q5EG47; -.
DR iPTMnet; Q5EG47; -.
DR PhosphoSitePlus; Q5EG47; -.
DR SwissPalm; Q5EG47; -.
DR EPD; Q5EG47; -.
DR jPOST; Q5EG47; -.
DR MaxQB; Q5EG47; -.
DR PaxDb; Q5EG47; -.
DR PRIDE; Q5EG47; -.
DR ProteomicsDB; 286040; -.
DR Antibodypedia; 3564; 1478 antibodies from 46 providers.
DR DNASU; 105787; -.
DR Ensembl; ENSMUST00000051186; ENSMUSP00000063166; ENSMUSG00000050697.
DR GeneID; 105787; -.
DR KEGG; mmu:105787; -.
DR UCSC; uc007vct.1; mouse.
DR CTD; 5562; -.
DR MGI; MGI:2145955; Prkaa1.
DR VEuPathDB; HostDB:ENSMUSG00000050697; -.
DR eggNOG; KOG0583; Eukaryota.
DR GeneTree; ENSGT00940000158865; -.
DR HOGENOM; CLU_000288_59_3_1; -.
DR InParanoid; Q5EG47; -.
DR OMA; HHFTRPH; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q5EG47; -.
DR TreeFam; TF314032; -.
DR BRENDA; 2.7.11.26; 3474.
DR BRENDA; 2.7.11.27; 3474.
DR BRENDA; 2.7.11.31; 3474.
DR Reactome; R-MMU-1632852; Macroautophagy.
DR Reactome; R-MMU-380972; Energy dependent regulation of mTOR by LKB1-AMPK.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
DR BioGRID-ORCS; 105787; 9 hits in 82 CRISPR screens.
DR ChiTaRS; Prkaa1; mouse.
DR PRO; PR:Q5EG47; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q5EG47; protein.
DR Bgee; ENSMUSG00000050697; Expressed in granulocyte and 223 other tissues.
DR ExpressionAtlas; Q5EG47; baseline and differential.
DR Genevisible; Q5EG47; MM.
DR GO; GO:0016324; C:apical plasma membrane; ISO:MGI.
DR GO; GO:0030424; C:axon; IGI:ARUK-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:ARUK-UCL.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0030425; C:dendrite; IGI:ARUK-UCL.
DR GO; GO:0043025; C:neuronal cell body; IGI:ARUK-UCL.
DR GO; GO:0016607; C:nuclear speck; ISO:MGI.
DR GO; GO:0031588; C:nucleotide-activated protein kinase complex; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0050405; F:[acetyl-CoA carboxylase] kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0047322; F:[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004679; F:AMP-activated protein kinase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0035174; F:histone serine kinase activity; IDA:UniProtKB.
DR GO; GO:0019900; F:kinase binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0050321; F:tau-protein kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0015721; P:bile acid and bile salt transport; IEA:Ensembl.
DR GO; GO:0038183; P:bile acid signaling pathway; IEA:Ensembl.
DR GO; GO:0061762; P:CAMKK-AMPK signaling cascade; ISO:MGI.
DR GO; GO:0071277; P:cellular response to calcium ion; IGI:ARUK-UCL.
DR GO; GO:0071361; P:cellular response to ethanol; IEA:Ensembl.
DR GO; GO:0042149; P:cellular response to glucose starvation; IDA:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IGI:ARUK-UCL.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0031669; P:cellular response to nutrient levels; IDA:UniProtKB.
DR GO; GO:0071417; P:cellular response to organonitrogen compound; IEA:Ensembl.
DR GO; GO:0034599; P:cellular response to oxidative stress; IGI:ARUK-UCL.
DR GO; GO:0071380; P:cellular response to prostaglandin E stimulus; IGI:MGI.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0009631; P:cold acclimation; ISO:MGI.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0055089; P:fatty acid homeostasis; ISS:UniProtKB.
DR GO; GO:0019395; P:fatty acid oxidation; IMP:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IMP:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0008610; P:lipid biosynthetic process; IDA:UniProtKB.
DR GO; GO:1905691; P:lipid droplet disassembly; ISO:MGI.
DR GO; GO:0061744; P:motor behavior; ISO:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL.
DR GO; GO:1903944; P:negative regulation of hepatocyte apoptotic process; ISS:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISO:MGI.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB.
DR GO; GO:1904428; P:negative regulation of tubulin deacetylation; IGI:ARUK-UCL.
DR GO; GO:0070050; P:neuron cellular homeostasis; ISO:MGI.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:MGI.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISS:UniProtKB.
DR GO; GO:1903109; P:positive regulation of mitochondrial transcription; IMP:UniProtKB.
DR GO; GO:2000758; P:positive regulation of peptidyl-lysine acetylation; IGI:ARUK-UCL.
DR GO; GO:1903829; P:positive regulation of protein localization; IGI:ARUK-UCL.
DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; IMP:UniProtKB.
DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IMP:MGI.
DR GO; GO:1990044; P:protein localization to lipid droplet; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0120188; P:regulation of bile acid secretion; IEA:Ensembl.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IGI:ARUK-UCL.
DR GO; GO:0033135; P:regulation of peptidyl-serine phosphorylation; IMP:MGI.
DR GO; GO:0062028; P:regulation of stress granule assembly; IGI:ARUK-UCL.
DR GO; GO:0060627; P:regulation of vesicle-mediated transport; ISO:MGI.
DR GO; GO:1904486; P:response to 17alpha-ethynylestradiol; IEA:Ensembl.
DR GO; GO:0014823; P:response to activity; ISO:MGI.
DR GO; GO:0031000; P:response to caffeine; ISO:MGI.
DR GO; GO:1901563; P:response to camptothecin; IMP:UniProtKB.
DR GO; GO:0010332; P:response to gamma radiation; IMP:UniProtKB.
DR GO; GO:0042542; P:response to hydrogen peroxide; IMP:UniProtKB.
DR GO; GO:0009411; P:response to UV; IMP:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd12199; AMPKA1_C; 1.
DR CDD; cd14403; UBA_AID_AAPK1; 1.
DR InterPro; IPR032270; AMPK_C.
DR InterPro; IPR039137; AMPKA1_C.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR028797; PRKAA1_UBA.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF16579; AdenylateSensor; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF103243; SSF103243; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Autophagy; Biological rhythms;
KW Cholesterol biosynthesis; Cholesterol metabolism; Chromatin regulator;
KW Cytoplasm; Fatty acid biosynthesis; Fatty acid metabolism; Kinase;
KW Lipid biosynthesis; Lipid metabolism; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation;
KW Wnt signaling pathway.
FT CHAIN 1..559
FT /note="5'-AMP-activated protein kinase catalytic subunit
FT alpha-1"
FT /id="PRO_0000085590"
FT DOMAIN 27..279
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 302..381
FT /note="AIS"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT REGION 485..536
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 485..531
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 150
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 33..41
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 56
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 32
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 183
FT /note="Phosphothreonine; by LKB1 and CaMKK2"
FT /evidence="ECO:0000269|PubMed:15980064,
FT ECO:0000269|PubMed:16054095, ECO:0000269|PubMed:16308421"
FT MOD_RES 355
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 356
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 360
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 368
FT /note="Phosphothreonine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 382
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 397
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 486
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 488
FT /note="Phosphothreonine; by ULK1"
FT /evidence="ECO:0000250|UniProtKB:P54645"
FT MOD_RES 490
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 496
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319"
FT MOD_RES 508
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 524
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MOD_RES 527
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13131"
FT MUTAGEN 168
FT /note="D->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:15878856,
FT ECO:0000269|PubMed:21258367"
FT CONFLICT 11..12
FT /note="Missing (in Ref. 2; AAW79567)"
FT /evidence="ECO:0000305"
FT STRAND 27..35
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 37..46
FT /evidence="ECO:0007829|PDB:5UFU"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 52..59
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 60..65
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 69..81
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 90..95
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 97..105
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 108..111
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 112..118
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 124..142
FT /evidence="ECO:0007829|PDB:5UFU"
FT TURN 143..145
FT /evidence="ECO:0007829|PDB:5UFU"
FT TURN 153..155
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 156..158
FT /evidence="ECO:0007829|PDB:5UFU"
FT STRAND 164..166
FT /evidence="ECO:0007829|PDB:5UFU"
FT TURN 188..190
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 193..196
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 204..220
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 230..238
FT /evidence="ECO:0007829|PDB:5UFU"
FT HELIX 250..259
FT /evidence="ECO:0007829|PDB:5UFU"
FT TURN 264..266
FT /evidence="ECO:0007829|PDB:5UFU"
SQ SEQUENCE 559 AA; 63929 MW; 08632503663D395B CRC64;
MRRLSSWRKM ATAEKQKHDG RVKIGHYILG DTLGVGTFGK VKVGKHELTG HKVAVKILNR
QKIRSLDVVG KIRREIQNLK LFRHPHIIKL YQVISTPSDI FMVMEYVSGG ELFDYICKNG
RLDEKESRRL FQQILSGVDY CHRHMVVHRD LKPENVLLDA HMNAKIADFG LSNMMSDGEF
LRTSCGSPNY AAPEVISGRL YAGPEVDIWS SGVILYALLC GTLPFDDDHV PTLFKKICDG
IFYTPQYLNP SVISLLKHML QVDPMKRAAI KDIREHEWFK QDLPKYLFPE DPSYSSTMID
DEALKEVCEK FECSEEEVLS CLYNRNHQDP LAVAYHLIID NRRIMNEAKD FYLATSPPDS
FLDDHHLTRP HPERVPFLVA ETPRARHTLD ELNPQKSKHQ GVRKAKWHLG IRSQSRPNDI
MAEVCRAIKQ LDYEWKVVNP YYLRVRRKNP VTSTFSKMSL QLYQVDSRTY LLDFRSIDDE
ITEAKSGTAT PQRSGSISNY RSCQRSDSDA EAQGKPSDVS LTSSVTSLDS SPVDVAPRPG
SHTIEFFEMC ANLIKILAQ
