Q09136 (AAPK1_PIG) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
5'-AMP-activated protein kinase catalytic subunit alpha-1
Short name=AMPK subunit alpha-1
EC=2.7.11.1

Alternative name(s):
AMPK 63 kDa subunit
Acetyl-CoA carboxylase kinase
Short name=ACACA kinase
EC=2.7.11.27
Hydroxymethylglutaryl-CoA reductase kinase
Short name=HMGCR kinase
EC=2.7.11.31
Tau-protein kinase PRKAA1
EC=2.7.11.26

Gene names

Name:	PRKAA1
Synonyms:	AMPK1

Organism

Sus scrofa (Pig) [Reference proteome]

Taxonomic identifier

9823 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Laurasiatheria › Cetartiodactyla › Suina › Suidae › Sus

Protein attributes

Sequence length	385 AA.
Sequence status	Fragments.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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: 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 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
Catalytic activity	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.
Cofactor	Magnesium By similarity.
Enzyme regulation	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.
Subunit structure	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.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: In response to stress, recruited by p53/TP53 to specific promoters By similarity.
Induction	By AMP.
Domain	The AIS (autoinhibitory sequence) region some sequence similarity with the ubiquitin-associated domains and represses kinase activity By similarity.
Post-translational modification	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.
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Autophagy Biological rhythms Cholesterol biosynthesis Cholesterol metabolism Fatty acid biosynthesis Fatty acid metabolism Lipid biosynthesis Lipid metabolism Steroid biosynthesis Steroid metabolism Sterol biosynthesis Sterol metabolism Transcription Transcription regulation Wnt signaling pathway
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Chromatin regulator Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW autophagy Inferred from electronic annotation. Source: UniProtKB-KW cellular response to glucose starvation Inferred from sequence or structural similarity. Source: UniProtKB cholesterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW fatty acid biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW fatty acid homeostasis Inferred from sequence or structural similarity. Source: UniProtKB glucose homeostasis Inferred from sequence or structural similarity. Source: UniProtKB lipid biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of TOR signaling cascade Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of lipid catabolic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of autophagy Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of glycolysis Inferred from sequence or structural similarity. Source: UniProtKB regulation of circadian rhythm Inferred from sequence or structural similarity. Source: UniProtKB regulation of energy homeostasis Inferred from sequence or structural similarity. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW rhythmic process Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	AMP-activated protein kinase complex Inferred from sequence or structural similarity. Source: UniProtKB cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	AMP-activated protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB ATP binding Inferred from electronic annotation. Source: UniProtKB-KW [acetyl-CoA carboxylase] kinase activity Inferred from electronic annotation. Source: EC [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity Inferred from electronic annotation. Source: EC chromatin binding Inferred from sequence or structural similarity. Source: UniProtKB histone serine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW tau-protein kinase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	‹1 – ›385	›385	5'-AMP-activated protein kinase catalytic subunit alpha-1		PRO_0000085591
Regions
	Domain	‹1 – 229	›229	Protein kinase
	Nucleotide binding	15 – ›22	›8	ATP By similarity
	Region	252 – 297	46	AIS By similarity
Sites
	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	134	1	Phosphoserine 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
Experimental info
	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
	Non-terminal residue	1	1
	Non-terminal residue	385	1

Sequences

	Sequence		Length	Mass (Da)
	Q09136 [UniParc]. Last modified September 2, 2008. Version 2. Checksum: A9B4BC0C935A85A6	FASTA	385	44,226
	10 20 30 40 50 60 DGRVKIGHYI LGDTLGVGTF GKRREIQNLK LFRHPHIIKL YQVISTPSDI FMVMEYVSGG 70 80 90 100 110 120 ELFDYICKNG RLDEKESRRL FQQILSGVDY CHRHMVVHRD LKPENVLLDA HMNAKIADFG 130 140 150 160 170 180 LSNMMSDGEF LRTSCGSPNY AAPEVISGRL YAGPEVDIWS SGVILYALLC GTLPFDDDHV 190 200 210 220 230 240 PTLFKKICDG IFYTPQYLNP SVISLLKHML QVDPMKRATI KDIREHEWFK QDLPKYLFPE 250 260 270 280 290 300 DPSYSXTMID DEALKQDPLA VAYHLIIDNR DFYLATSPPD SFLDDHHLTR VPFLVAETPR 310 320 330 340 350 360 DELNPQKXKH QGVRKAKXHL GIRQLDYEXK VVNPYYLRVR RKKMSLQLYQ VDSRTYLLDF 370 380 RSIDDXIDAE AQGKSSEASL TXSVT

References

[1]	"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. Tissue: Liver.
[2]	"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. Tissue: Liver.
[3]	"Effect of dietary hemicellulose on growth and energy metabolism of growing pigs." Weber T.E. Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 23-243.

Cross-references

Sequence databases
EMBL GenBank DDBJ	EU622639 mRNA. Translation: ACC78144.1.
PIR	A49958.
UniGene	Ssc.26892.
3D structure databases
ProteinModelPortal	Q09136.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Phylogenomic databases
HOVERGEN	HBG050432.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. Partial match. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

AAPK1_PIG

Accession

Primary (citable) accession number: Q09136
Secondary accession number(s): B2MV24

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	September 2, 2008
Last modified:	April 3, 2013
This is version 88 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program