Structure of an AMPK complex in an inactive, ATP-bound state.
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
23 07 2021
23 07 2021
Historique:
received:
12
09
2020
revised:
31
03
2021
accepted:
07
06
2021
entrez:
26
8
2021
pubmed:
27
8
2021
medline:
11
9
2021
Statut:
ppublish
Résumé
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° 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.
Identifiants
pubmed: 34437114
pii: 373/6553/413
doi: 10.1126/science.abe7565
pmc: PMC8428800
mid: NIHMS1736008
doi:
Substances chimiques
Immunoglobulin Fab Fragments
0
adenosine 5'-O-(3-thiotriphosphate)
35094-46-3
Adenosine Monophosphate
415SHH325A
Adenosine Triphosphate
8L70Q75FXE
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
413-419Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM117372
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM129436
Pays : United States
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
Nature. 2013 Jun 13;498(7453):E8-10
pubmed: 23765502
Pediatr Res. 2007 Oct;62(4):499-504
pubmed: 17667862
Structure. 2014 Aug 5;22(8):1161-1172
pubmed: 25066137
Physiol Rev. 2009 Jul;89(3):1025-78
pubmed: 19584320
BMC Syst Biol. 2015 Mar 11;9:13
pubmed: 25890336
Mol Cell. 2013 Feb 7;49(3):379-87
pubmed: 23395268
Chem Biol. 2014 May 22;21(5):619-27
pubmed: 24746562
Mol Cell Proteomics. 2011 Jan;10(1):M110.002212
pubmed: 20736410
J R Soc Interface. 2018 Jan;15(138):
pubmed: 29343628
Mol Cell. 2017 Jun 15;66(6):789-800
pubmed: 28622524
Cell Res. 2015 Jan;25(1):50-66
pubmed: 25412657
Eur J Biochem. 1989 Dec 8;186(1-2):129-36
pubmed: 2598924
J Biol Chem. 2019 Jan 18;294(3):953-967
pubmed: 30478170
Structure. 2013 Nov 5;21(11):1942-53
pubmed: 24076403
J Biol Chem. 2017 Sep 29;292(39):16310-16320
pubmed: 28821611
Cell Metab. 2013 Oct 1;18(4):556-66
pubmed: 24093679
J Clin Invest. 2001 Oct;108(8):1167-74
pubmed: 11602624
J Biol Chem. 2018 Nov 2;293(44):16994-17007
pubmed: 30206123
Cell Res. 2013 Oct;23(10):1237-40
pubmed: 23999859
Science. 2011 Jun 17;332(6036):1433-5
pubmed: 21680840
Mol Cell. 2020 Mar 5;77(5):951-969.e9
pubmed: 31995728
Cell Metab. 2013 Oct 1;18(4):546-55
pubmed: 24093678
Science. 2011 Jan 28;331(6016):456-61
pubmed: 21205641
Genes Dev. 2011 Sep 15;25(18):1895-908
pubmed: 21937710
Biochim Biophys Acta. 2010 Mar;1804(3):581-91
pubmed: 19778642
J Mol Biol. 2018 Feb 2;430(3):322-336
pubmed: 29277294
Nat Commun. 2013;4:3017
pubmed: 24352254
J Biol Chem. 2010 Jan 1;285(1):115-22
pubmed: 19892703
J Biol Chem. 2007 Nov 9;282(45):32549-60
pubmed: 17855357
Mol Cell. 2004 Sep 10;15(5):661-75
pubmed: 15350212
FEBS Lett. 1995 Dec 27;377(3):421-5
pubmed: 8549768
Nature. 2011 Apr 14;472(7342):230-3
pubmed: 21399626
Mol Cell Endocrinol. 2009 Jan 15;297(1-2):41-9
pubmed: 18611432
J Biol Chem. 2007 Nov 9;282(45):32539-48
pubmed: 17728241
Clin Sci (Lond). 2009 Apr;116(8):607-20
pubmed: 19275766
Autophagy. 2020 Oct;16(10):1871-1888
pubmed: 31983282
FEBS J. 2016 Aug;283(16):2987-3001
pubmed: 26934201
J Biol Chem. 2017 Jul 28;292(30):12653-12666
pubmed: 28615457
Elife. 2017 Oct 13;6:
pubmed: 29027899
Science. 2005 Dec 9;310(5754):1642-6
pubmed: 16308421