7m74

From Proteopedia

Jump to: navigation, search

ATP-bound AMP-activated protein kinase

Structural highlights

7m74 is a 7 chain structure with sequence from Escherichia coli, Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.93Å
Ligands:ADP, AMP, ATP, GLC, PRD_900001, TAK
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

AAPK1_HUMAN 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 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Publication Abstract from PubMed

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under energy stress, AMP stabilizes the active AMPK conformation, in which the kinase activation loop (AL) is protected from protein phosphatases, thus keeping the AL in its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits AMPK by increasing AL dynamics and accessibility. We developed conformation-specific antibodies to trap ATP-bound AMPK in a fully inactive, dynamic state and determined its structure at 3.5-angstrom resolution using cryo-electron microscopy. A 180 degrees rotation and 100-angstrom displacement of the kinase domain fully exposes the AL. On the basis of the structure and supporting biophysical data, we propose a multistep mechanism explaining how adenine nucleotides and pharmacological agonists modulate AMPK activity by altering AL phosphorylation and accessibility.

Structure of an AMPK complex in an inactive, ATP-bound state.,Yan Y, Mukherjee S, Harikumar KG, Strutzenberg TS, Zhou XE, Suino-Powell K, Xu TH, Sheldon RD, Lamp J, Brunzelle JS, Radziwon K, Ellis A, Novick SJ, Vega IE, Jones RG, Miller LJ, Xu HE, Griffin PR, Kossiakoff AA, Melcher K Science. 2021 Jul 23;373(6553):413-419. doi: 10.1126/science.abe7565. PMID:34437114[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Loading citation details..
Citations
reviews cite this structure
-1 more
other articles
No citations found

See Also

References

  1. ↑ Yang W, Hong YH, Shen XQ, Frankowski C, Camp HS, Leff T. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem. 2001 Oct 19;276(42):38341-4. Epub 2001 Aug 22. PMID:11518699 doi:10.1074/jbc.C100316200
  2. ↑ Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H. Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem Biophys Res Commun. 2001 Sep 21;287(2):562-7. PMID:11554766 doi:10.1006/bbrc.2001.5627
  3. ↑ Hallows KR, Kobinger GP, Wilson JM, Witters LA, Foskett JK. Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells. Am J Physiol Cell Physiol. 2003 May;284(5):C1297-308. Epub 2003 Jan 2. PMID:12519745 doi:10.1152/ajpcell.00227.2002
  4. ↑ Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003 Nov 26;115(5):577-90. PMID:14651849
  5. ↑ Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005 Apr 29;18(3):283-93. PMID:15866171 doi:10.1016/j.molcel.2005.03.027
  6. ↑ Lee JH, Koh H, Kim M, Kim Y, Lee SY, Karess RE, Lee SH, Shong M, Kim JM, Kim J, Chung J. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature. 2007 Jun 21;447(7147):1017-20. Epub 2007 May 7. PMID:17486097 doi:10.1038/nature05828
  7. ↑ Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem. 2007 Oct 12;282(41):30107-19. Epub 2007 Aug 20. PMID:17711846 doi:10.1074/jbc.M705325200
  8. ↑ McGee SL, van Denderen BJ, Howlett KF, Mollica J, Schertzer JD, Kemp BE, Hargreaves M. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes. 2008 Apr;57(4):860-7. doi: 10.2337/db07-0843. Epub 2008 Jan 9. PMID:18184930 doi:10.2337/db07-0843
  9. ↑ Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008 Apr 25;30(2):214-26. doi: 10.1016/j.molcel.2008.03.003. PMID:18439900 doi:http://dx.doi.org/10.1016/j.molcel.2008.03.003
  10. ↑ McDonald A, Fogarty S, Leclerc I, Hill EV, Hardie DG, Rutter GA. Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic beta-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement. Biochem Soc Trans. 2010 Feb;38(Pt 1):205-8. doi: 10.1042/BST0380205. PMID:20074060 doi:10.1042/BST0380205
  11. ↑ Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan KL, Shen J, Person MD, Kusewitt D, Mills GB, Kastan MB, Walker CL. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4153-8. doi: 10.1073/pnas.0913860107., Epub 2010 Feb 16. PMID:20160076 doi:10.1073/pnas.0913860107
  12. ↑ Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011 Jan 28;331(6016):456-61. doi: 10.1126/science.1196371. Epub 2010, Dec 23. PMID:21205641 doi:10.1126/science.1196371
  13. ↑ Yan Y, Mukherjee S, Harikumar KG, Strutzenberg TS, Zhou XE, Suino-Powell K, Xu TH, Sheldon RD, Lamp J, Brunzelle JS, Radziwon K, Ellis A, Novick SJ, Vega IE, Jones RG, Miller LJ, Xu HE, Griffin PR, Kossiakoff AA, Melcher K. Structure of an AMPK complex in an inactive, ATP-bound state. Science. 2021 Jul 23;373(6553):413-419. PMID:34437114 doi:10.1126/science.abe7565

Contents


PDB ID 7m74

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/7m74"
Personal tools