Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase
Abstract
:1. Introduction
2. Regulation by Phosphorylation
2.1. α-Subunit
2.1.1. Activation Loop
2.1.2. α-Linker
2.1.3. β-SID and ST Loop
2.2. β-Subunit
2.2.1. NH2-Terminal Domain
2.2.2. CBM
2.2.3. β-Linker
2.3. γ-Subunit
3. Other AMPK Modifications (Non-Phosphorylation)
3.1. Ubiquitination
3.2. Sumoylation
3.3. Acetylation
3.4. Methylation
3.5. Oxidative Modifications
4. Perspectives
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
α-RIM | α-regulatory subunit interacting motif |
AICAR | 5-aminoimadazole-4-carboxamide-1-β-D-ribofuranoside |
ACC | acetyl-CoA carboxylase |
ALD | adrenoleukodystrophy |
AMP | 5′-adenosine monophosphate |
AMPK | AMP-activated protein kinase |
ADaM | allosteric drug and metabolite |
ADP | 5′-adenosine diphosphate |
ATP | 5′-adenosine triphosphate |
α-γ-SBS | α-γ-subunit binding sequence |
BMMC | bone marrow–derived mast cells |
BR | BRAFi-resistant melanoma |
β-SID | β-subunit interacting domain |
CBM | carbohydrate binding module |
CaMKK | calcium/calmodulin-dependent kinase kinase |
CDK4 | cyclin-dependent kinase 4 |
CIDEA | cell death-inducing DFF45-like effector A |
CoA | coenzyme A |
CRBN | cereblon |
CRL4A | cullin-RING 4A |
DNA-PK | DNA-dependent protein kinase |
GID | glucose-induced degradation |
GSK3 | glycogen synthase kinase 3 |
HCC | hepatocellular carcinoma |
HPAEC | human pulmonary arterial endothelial cell |
HSL | hormone sensitive lipase |
HTP | high-throughput |
LKB1 | liver kinase B1 |
MAGE | melanoma antigens |
MEF | mouse embryonic fibroblast |
MKRN1 | makorin ring finger protein 1 |
MLK3 | mixed-linkage kinase 3 |
mTORC1 | mammalian (mechanistic) target of rapamycin complex 1 |
NTD | NH2-terminal domain |
PEDFR | pigment epithelium derived factor receptor |
PIAS4/γ | protein inhibitor of activated STAT protein 4/g |
PKA | protein kinase A |
PKC | protein kinase C |
PKD1 | protein kinase D1 |
PPARγ | peroxisome proliferator activated receptor γ |
PP2A | protein phosphatase 2A |
PP2C | protein phosphatase 2C |
PPM1E | Mg2+/Mn2+-dependent protein phosphatase 1E |
PTM | post-translational modification |
RNF44 | RING finger 44 |
ROS | reactive oxygen species |
Sip2 | SNF1-interacting protein 2 |
SIK | salt-inducible kinase |
Snf1 | sucrose non-fermenting protein 1 |
STIM1 | stromal interaction molecule 1 |
SUMO | Small Ubiquitin-like Modifier |
TAK1 | transforming growth factor-β-activated kinase 1 |
TNFα | tumour necrosis factor α |
TRIM27 | tripartite motif-containing protein 27 |
TSC2 | tuberous sclerosis complex 2 |
Ub | ubiquitin |
UBE2O | E2/E3 hybrid ubiquitin-protein ligase |
ULK1 | Unc-51-like kinase 1 |
USP10 | ubiquitin-specific-processing protease 10 |
UPS | ubiquitin-proteasome system |
VRK1 | vaccinia-related kinase 1 |
WWP1 | WW domain-containing protein 1 |
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Isoform/Residue | Location | Regulatory Function | Notes | Kinase | Primary Ref. |
---|---|---|---|---|---|
α-subunit Uniprot IDs α1: Q13131-1 (numbering starts from initiation Met10, most commonly used in the field); α2: P54646-1 | |||||
α1-T174/α2-T172 [30] | Activation loop | Activatory | Fully validated upstream kinases | LKB1 | [31,32] |
CaMKK2 | [33] [34] | ||||
Less well validated upstream kinases | TAK1 | [35,36] | |||
MLK3 | [37] | ||||
CaMKK1 | [34] | ||||
VRK1 | [38] | ||||
α1-S175/α2-S173 | Activation loop | Inhibitory | Suppresses T172 phosphorylation | PKA | [39] |
α1-S347/α2-S345 | α-linker | Inhibitory | Suppresses T172 phosphorylation | CDK4 | [40] |
mTORC1 | [41] | ||||
α1-Y432/α2-Y436 | β-SID | Inhibitory | Fyn | [42] | |
α1-T481/α2-T485 | ST loop | Inhibitory | Promotes T172 dephosphorylation | GSK3α/β | [43] |
CDK4 (only α2-T485?) | [40] | ||||
α1-S487/α2-S491 [44] | ST loop | Inhibitory | Suppresses T172 phosphorylation | autophos. (α2-S491 more than α1-S487) | [45] |
Akt/PKB (α1-S487 more than α2-S491) | [46] [45] [47] | ||||
PKA (only α1-S487) | [39,48] | ||||
PKC (only α1-S487?) | [44] | ||||
ERK1/2 | [49] | ||||
IKKβ | [50] | ||||
p70S6K | [51] | ||||
PKD1 (only α2-S491?) | [52] | ||||
β-subunit Uniprot IDs β1: Q9Y478-1; β2: O43741-1 | |||||
β1-S24/25 [53] | NH2-terminus | Localisation | S24/25A promotes nuclear transport [54] | Akt/PKB | [39] |
β1/2-S108 [53] | CBM | Activatory | Stabilises ADaM site and sensitises AMPK to ligands [13,55,56]; β1-S108A reduced basal activity [54] | cis-autophos. | [53] |
ULK1 (β1-S108 only) | [57] | ||||
β1/2-T148 | CBM | Localisation | T148D destabilises glycogen complex | autophos. | [58] |
β1-S182/ β2-S184 [53] | β-linker | Localisation | β1-S182A promotes nuclear transport; skeletal muscle: β1-pS182 stoichiometric; β2-pS184 substoichiometric, 41 HTPs | [53,54,59] | |
γ-subunit Uniprot ID γ1: P54619-1 | |||||
γ1-S192 | CBS2-3 linker | Activatory | γ1-S192A (with γ1-T284A) attenuates lysosome transport | DNA-PK | [60] |
γ1-T284 | CBS4 | Activatory | γ1-T284A (with γ1-S192A) attenuates lysosome transport | DNA-PK | [60] |
Isoform/Residue | Location | Notes | Kinase | Primary Ref. |
---|---|---|---|---|
α-subunit Uniprot IDs α1: Q13131-1 (numbering starts from initiation Met10, most commonly used in the field); α2: P54646-1 | ||||
α1-S178/α2-S176 | Activation loop | 18 HTPs | [29] | |
α1-T260 | Kinase domain C-lobe | In vitro phosphorylation | autophos. | [44] |
α1-S351/T359 | α-linker | In vitro phosphorylation | ULK1 | [61] |
α1-T373 | α-linker | 30 HTPs | [29] | |
α2-S377 | α-linker | 28 HTPs; in vitro phosphorylation | CDK4 | [29,40] |
α1-T379 | α-linker | In vitro phosphorylation | autophos. | [62] |
α1-S388 | α-linker | In vitro phosphorylation | ULK1 | [61] |
α1-S473 | ST loop | In vitro phosphorylation | GSK3α/β | [43] |
α1-S477 | ST loop | In vitro phosphorylation | GSK3α/β | [43] |
ULK1 | [61] | |||
α1-T479 | ST loop | In vitro phosphorylation | ULK1 | [61] |
α1-S497 | ST loop | In vitro phosphorylation | PKA | [39] |
α1-S499 | ST loop | 27 HTPs ; in vitro phosphorylation | PKA | [29,39] |
α2-S529 | ST loop | In vitro phosphorylation | CDK4 | [40] |
β-subunit Uniprot IDs β1: Q9Y478-1; β2: O43741-1 | ||||
β2-S39 | NH2-terminus | In vitro phosphorylation; 22 HTPs | ULK1 | [61] |
β2-T40 | NH2-terminus | In vitro phosphorylation | ULK1 | [61] |
β1-S49 | NH2-terminus | In vitro phosphorylation | ULK1 | [57] |
β2-S69 | CBM | In vitro phosphorylation | ULK1 | [61] |
β1-T80 | CBM | In vitro phosphorylation | autophos. | [62] |
β1-S96 | CBM | In vitro phosphorylation | autophos. | [44] |
ULK1 | [57] | |||
β1-S101 | CBM | In vitro phosphorylation | autophos. | [44] |
β1-T158 | CBM | In vitro phosphorylation | autophos. | [62] |
β1-S170 | αC-interacting helix | In vitro phosphorylation | ULK1 | [57] |
β1/2-S174 | αC-interacting helix | In vitro phosphorylation | autophos. (β1-S174) | [62] |
ULK1 (β2-S174) | [61] | |||
β1-S177 | β-linker | In vitro phosphorylation | autophos. | [62] |
γ-subunit Uniprot IDs γ1: P54619-1; γ2: Q9UGJ0-1 | ||||
γ1-S261/T263 | CBS3 | In vitro phosphorylation | ULK1 | [57,61] |
γ1-S270 | CBS3-4 linker | In vitro phosphorylation | ULK1 | [57,61] |
γ1-Y272 | CBS3-4 linker | 65 HTPs | [29] | |
γ2-S65 | NH2-terminus | 33 HTPs | [29] | |
γ2-S71 | NH2-terminus | 25 HTPs | [29] | |
γ2-S122 | NH2-terminus | 16 HTPs | [29] | |
γ2-S196 | NH2-terminus | 25 HTPs | [29] |
Isoform/Residue | Location | Notes | Modifying Enzyme | Primary Ref. |
---|---|---|---|---|
Ubiquitination | ||||
α1/α2 | Systemic metabolism | MKRN1 | [110] | |
α1-K62/276/388/476 α2-K60/379/391/470 | K63-linked deubiquitination promotes AMPK activity | USP10 | [111] | |
α1/α2 | Increased allergic mediator secretion from BMMCs | CRL4A, enhanced by CRBN | [112] | |
α1/α2 | Suppression of autophagy during prolonged starvation | GID ubiquitin ligase complex | [113] | |
α1/α2 | Mediated by PEDF/PEDFR/PPARγ axis | [114] | ||
α1 | Reduced AMPK expression and bioenergetic profile in ALD fibroblasts and lymphocytes | [115] | ||
α1 | Cancer-specific | MAGE-A3/6-TRIM28 | [116] | |
α1 | Promotes α1 degradation in BRAFi-resistant melanoma cells | RNF44 | [117] | |
α1 | PEDF promotes α1 degradation to disturb lipid metabolism in HCC cells | [118] | ||
α2 | USP9X-mediated α2 ubiquitination in C2C12 cells suppressed by calorie restriction serum | [119] | ||
α2 | Downregulates α2 in C2C12 cells | WWP1 | [120] | |
α1-K387/α2-K391 | α-linker | 4 HTPs | [29] | |
α1-K476 | ST loop | 5 HTPs | [29] | |
α2-K470 | β-SID | Cancer progression | UBE2O | [121] |
β1 | Promotes β1 degradation in brown adipose tissue and adipocytes to suppress fat oxidation | Promoted by Cidea | [122] | |
β1 | Induced by E4BP4, promoting degradation | [123] | ||
β2 | K63-linked Ub chains; accumulation, possibly associated with localisation | Laforin-malin complex | [124] | |
γ1 | Promotes γ1 degradation through interaction with α, exacerbating high fat diet-induced metabolic defects | CRL4ACRBN | [125,126,127] | |
γ1-K234 | CBS3 | 6 HTPs | [29] | |
γ1-K264 | CBS3 | 7 HTPs | [29] | |
γ1-K329 | CBS4 | 6 HTPs | [29] | |
Sumoylation | ||||
α1-K109/α2 | Kinase domain C-lobe | Down regulates AMPK activity towards mTORC1 signalling | PIAS4 | [128] |
β2 | Increases AMPK activity; competes with ubiquitination | PIAS4 | [129] | |
Acetylation | ||||
α1-K31 | Kinase domain N-lobe (ADaM site) | K31 stabilizes ADaM site | [130] | |
α1-K33 | Kinase domain N-lobe (ADaM site) | K33 stabilizes ADaM site | [130] | |
α1-K71/α2-K69 | Kinase domain C-helix | 4 HTPs | [29] | |
γ1 | NH2-terminus | Deduced from rat liver prep ToF-MS | NatB complex? | [53] |
γ1-K264 | CBS3 | 3 HTPs | [29] | |
γ2-K9/K10 | NH2-terminus | 1 HTP | [130] | |
Methylation | ||||
α2-R227 | Kinase domain C-lobe | 1 HTPs; monomethylation | [29,131] | |
γ1-K34 | NH2-terminus | 1 HTP | [29,132] | |
γ2-K62 | NH2-terminus | 1 HTP | [29] | |
Oxidation | ||||
α1-C176 | Activation loop | s-nitrosylation; in vitro using HPAEC and HEK lysates | [133,134] | |
α1-C299/304 | AID | Activating; C304 may be a specific target for s-glutathionylation | [135] | |
α1-C416 | β-SID | s-nitrosylation; in vitro using HEK lysates | [134] | |
α2-C130/174 | Kinase domain C-lobe | Inhibitory; interferes with AMPK kinase interactions. Suppressed by Trx1 | [136] |
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Ovens, A.J.; Scott, J.W.; Langendorf, C.G.; Kemp, B.E.; Oakhill, J.S.; Smiles, W.J. Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase. Int. J. Mol. Sci. 2021, 22, 1229. https://doi.org/10.3390/ijms22031229
Ovens AJ, Scott JW, Langendorf CG, Kemp BE, Oakhill JS, Smiles WJ. Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase. International Journal of Molecular Sciences. 2021; 22(3):1229. https://doi.org/10.3390/ijms22031229
Chicago/Turabian StyleOvens, Ashley J., John W. Scott, Christopher G. Langendorf, Bruce E. Kemp, Jonathan S. Oakhill, and William J. Smiles. 2021. "Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase" International Journal of Molecular Sciences 22, no. 3: 1229. https://doi.org/10.3390/ijms22031229