PH domain-mediated autoinhibition and oncogenic activation of Akt.
NMR
biochemistry
chemical biology
enzymes
human
molecular biophysics
phosphorylation
protein kinase
protein semisynthesis
structural biology
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
15 08 2022
15 08 2022
Historique:
received:
12
05
2022
accepted:
09
08
2022
pubmed:
16
8
2022
medline:
30
8
2022
entrez:
15
8
2022
Statut:
epublish
Résumé
Akt is a Ser/Thr protein kinase that plays a central role in metabolism and cancer. Regulation of Akt's activity involves an autoinhibitory intramolecular interaction between its pleckstrin homology (PH) domain and its kinase domain that can be relieved by C-tail phosphorylation. PH domain mutant E17K Akt is a well-established oncogene. Previously, we reported that the conformation of autoinhibited Akt may be shifted by small molecule allosteric inhibitors limiting the mechanistic insights from existing X-ray structures that have relied on such compounds (Chu et al., 2020). Here, we discover unexpectedly that a single mutation R86A Akt exhibits intensified autoinhibitory features with enhanced PH domain-kinase domain affinity. Structural and biochemical analysis uncovers the importance of a key interaction network involving Arg86, Glu17, and Tyr18 that controls Akt conformation and activity. Our studies also shed light on the molecular basis for E17K Akt activation as an oncogenic driver.
Identifiants
pubmed: 35968932
doi: 10.7554/eLife.80148
pii: 80148
pmc: PMC9417420
doi:
pii:
Substances chimiques
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM136859
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221830
Pays : United States
Organisme : NIBIB NIH HHS
ID : P41 EB002026
Pays : United States
Organisme : NCI NIH HHS
ID : R29 CA074305
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA074305
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA242461
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA241105
Pays : United States
Informations de copyright
© 2022, Bae, Viennet et al.
Déclaration de conflit d'intérêts
HB, TV, EP, NC, AS, ME, HA No competing interests declared, PC Senior editor, eLife
Références
Annu Rev Pathol. 2009;4:127-50
pubmed: 18767981
Biochemistry. 2009 Jul 21;48(28):6624-32
pubmed: 19518076
J Biol Chem. 2018 Jul 6;293(27):10744-10756
pubmed: 29773654
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6705-10
pubmed: 9618476
Mol Cell. 2002 Jun;9(6):1227-40
pubmed: 12086620
Cancer Cell. 2003 Oct;4(4):257-62
pubmed: 14585353
Elife. 2013 Jul 09;2:e00691
pubmed: 23853711
Nat Rev Clin Oncol. 2018 May;15(5):273-291
pubmed: 29508857
J Magn Reson. 2005 Jun;174(2):331-4
pubmed: 15862252
Sci Signal. 2012 May 08;5(223):ra37
pubmed: 22569334
Cell. 2018 Aug 9;174(4):897-907.e14
pubmed: 30078705
Annu Rev Biochem. 1999;68:965-1014
pubmed: 10872470
Proteins. 2005 Jun 1;59(4):687-96
pubmed: 15815974
Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3940-E3949
pubmed: 29632185
Biochem J. 2003 Nov 1;375(Pt 3):531-8
pubmed: 12964941
J Med Chem. 2012 Jun 14;55(11):5291-310
pubmed: 22533986
Mol Cell. 2005 Apr 1;18(1):13-24
pubmed: 15808505
Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):E1120-7
pubmed: 22031698
Biophys J. 2017 Jul 25;113(2):393-401
pubmed: 28746850
Angew Chem Int Ed Engl. 2019 Dec 19;58(52):18823-18829
pubmed: 31584233
Cancer Lett. 2013 Jul 10;335(1):9-18
pubmed: 23454242
Mol Cancer. 2019 Feb 19;18(1):26
pubmed: 30782187
J Hematol Oncol. 2021 Aug 21;14(1):128
pubmed: 34419139
Science. 1991 Aug 9;253(5020):657-61
pubmed: 1871600
Methods Enzymol. 2015;559:1-15
pubmed: 26096499
Nature. 2014 Apr 24;508(7497):541-5
pubmed: 24670654
Biol Open. 2012 Sep 15;1(9):857-62
pubmed: 23213479
Nature. 2021 Aug;596(7873):583-589
pubmed: 34265844
Nucleic Acids Res. 2022 Jan 7;50(D1):D439-D444
pubmed: 34791371
J Biomol NMR. 1995 Nov;6(3):277-93
pubmed: 8520220
Curr Opin Struct Biol. 2019 Dec;59:47-53
pubmed: 30901610
Anal Chem. 2015 Apr 21;87(8):4370-6
pubmed: 25799115
J Am Chem Soc. 2018 Aug 1;140(30):9374-9378
pubmed: 30016585
Gene. 1997 Jun 19;192(2):271-81
pubmed: 9224900
PLoS Biol. 2009 Jan 20;7(1):e17
pubmed: 19166270
Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):
pubmed: 34385319
Nat Methods. 2019 Apr;16(4):333-340
pubmed: 30858598
Nat Struct Mol Biol. 2021 Oct;28(10):858-868
pubmed: 34625746
Biochemistry. 2008 Nov 25;47(47):12260-9
pubmed: 18954143
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Curr Biol. 1997 Apr 1;7(4):261-9
pubmed: 9094314
Cell. 2017 Apr 20;169(3):381-405
pubmed: 28431241
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2598-603
pubmed: 20133737
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19368-73
pubmed: 23134728
PLoS One. 2010 Sep 23;5(9):e12913
pubmed: 20886116
J Biomol NMR. 2007 Dec;39(4):275-89
pubmed: 17955183
EMBO J. 1996 Dec 2;15(23):6541-51
pubmed: 8978681
Nat Commun. 2018 Aug 1;9(1):3014
pubmed: 30069002
J Biol Chem. 1996 Dec 6;271(49):31372-8
pubmed: 8940145
Nucleic Acids Res. 2015 Jul 27;43(13):6486-99
pubmed: 26101257
ACS Chem Biol. 2022 Jan 21;17(1):68-76
pubmed: 34941261
Nature. 2007 Jul 26;448(7152):439-44
pubmed: 17611497
Nat Rev Mol Cell Biol. 2018 Sep;19(9):547-562
pubmed: 29858604
Nat Rev Cancer. 2020 Feb;20(2):74-88
pubmed: 31686003
Science. 2005 Feb 18;307(5712):1098-101
pubmed: 15718470
Elife. 2020 Aug 03;9:
pubmed: 32744507
J Biol Chem. 2008 Jan 25;283(4):1882-92
pubmed: 18042541
Nat Struct Biol. 2002 Dec;9(12):940-4
pubmed: 12434148
Expert Opin Investig Drugs. 2019 Nov;28(11):977-988
pubmed: 31594388
J Biol Chem. 2006 May 19;281(20):13949-56
pubmed: 16540465
Mol Cell. 2017 Feb 2;65(3):416-431.e6
pubmed: 28157504