CPLM-008876

Genbank Nucleotide ID

5'-AMP-activated protein kinase catalytic subunit alpha-2

Protein Synonyms/Alias

AMPK subunit alpha-2; Acetyl-CoA carboxylase kinase; ACACA kinase; Hydroxymethylglutaryl-CoA reductase kinase; HMGCR kinase

Homo sapiens (Human)

Position	Peptide	Type	References
45	TGHKVAVKILNRQKI	ubiquitination	[1, 2]
69	KREIQNLKLFRHPHI	acetylation	[3, 4, 5]
141	MVVHRDLKPENVLLD	ubiquitination	[1]
154	LDAHMNAKIADFGLS	ubiquitination	[6]
401	SLAVKKAKWHLGIRS	ubiquitination	[1]

[1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
[2] Integrated proteomic analysis of post-translational modifications by serial enrichment.
Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
[3] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
[4] Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response.
Beli P, Lukashchuk N, Wagner SA, Weinert BT, Olsen JV, Baskcomb L, Mann M, Jackson SP, Choudhary C.
Mol Cell. 2012 Apr 27;46(2):212-25. [PMID: 22424773]
[5] Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3.
Sol EM, Wagner SA, Weinert BT, Kumar A, Kim HS, Deng CX, Choudhary C.
PLoS One. 2012;7(12):e50545. [PMID: 23236377]
[6] Global identification of modular cullin-RING ligase substrates.
Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]

Functional Description

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 phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.

DOMAIN 16 268 Protein kinase.
NP_BIND 22 30 ATP (By similarity).
REGION 291 376 AIS (By similarity).
ACT_SITE 139 139 Proton acceptor (By similarity).
BINDING 45 45 ATP (By similarity).
MOD_RES 172 172 Phosphothreonine; by LKB1 and CaMKK2.
MOD_RES 173 173 Phosphoserine (By similarity).
MOD_RES 258 258 Phosphothreonine (By similarity).
MOD_RES 377 377 Phosphoserine.
MOD_RES 491 491 Phosphoserine (By similarity).
MOD_RES 500 500 Phosphoserine (By similarity).

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.

UniProt (SWISSPROT/TrEMBL); GenBank; EMBL

GO:0005829; C:cytosol; TAS:Reactome.
GO:0005654; C:nucleoplasm; TAS:Reactome.
GO:0050405; F:[acetyl-CoA carboxylase] kinase activity; IEA:EC.
GO:0047322; F:[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity; IEA:EC.
GO:0004679; F:AMP-activated protein kinase activity; IDA:UniProtKB.
GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO:0003682; F:chromatin binding; ISS:UniProtKB.
GO:0035174; F:histone serine kinase activity; ISS:UniProtKB.
GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO:0006914; P:autophagy; IEA:UniProtKB-KW.
GO:0006853; P:carnitine shuttle; TAS:Reactome.
GO:0007050; P:cell cycle arrest; TAS:Reactome.
GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
GO:0016044; P:cellular membrane organization; TAS:Reactome.
GO:0042149; P:cellular response to glucose starvation; ISS:UniProtKB.
GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
GO:0055089; P:fatty acid homeostasis; ISS:UniProtKB.
GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB.
GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
GO:0032007; P:negative regulation of TOR signaling cascade; ISS:UniProtKB.
GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
GO:0045821; P:positive regulation of glycolysis; ISS:UniProtKB.
GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
GO:2000505; P:regulation of energy homeostasis; ISS:UniProtKB.
GO:0042304; P:regulation of fatty acid biosynthetic process; TAS:Reactome.
GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
GO:0044281; P:small molecule metabolic process; TAS:Reactome.
GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW.

IPR011009; Kinase-like_dom.
IPR000719; Prot_kinase_cat_dom.
IPR017441; Protein_kinase_ATP_BS.
IPR002290; Ser/Thr_dual-sp_kinase_dom.
IPR008271; Ser/Thr_kinase_AS.

PS00107; PROTEIN_KINASE_ATP
PS50011; PROTEIN_KINASE_DOM
PS00108; PROTEIN_KINASE_ST