The structural determinants of PH domain-mediated regulation of Akt revealed by segmental labeling.
NMR
PH domain
biochemistry
chemical biology
human
phosphorylation
protein kinase
signaling
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
03 08 2020
03 08 2020
Historique:
received:
20
05
2020
accepted:
03
08
2020
pubmed:
4
8
2020
medline:
20
2
2021
entrez:
4
8
2020
Statut:
epublish
Résumé
Akt is a critical protein kinase that governs cancer cell growth and metabolism. Akt appears to be autoinhibited by an intramolecular interaction between its N-terminal pleckstrin homology (PH) domain and kinase domain, which is relieved by C-tail phosphorylation, but the precise molecular mechanisms remain elusive. Here, we use a combination of protein semisynthesis, NMR, and enzymological analysis to characterize structural features of the PH domain in its autoinhibited and activated states. We find that Akt autoinhibition depends on the length/flexibility of the PH-kinase linker. We identify a role for a dynamic short segment in the PH domain that appears to regulate autoinhibition and PDK1-catalyzed phosphorylation of Thr308 in the activation loop. We determine that Akt allosteric inhibitor MK2206 drives distinct PH domain structural changes compared to baseline autoinhibited Akt. These results highlight how the conformational plasticity of Akt governs the delicate control of its catalytic properties.
Identifiants
pubmed: 32744507
doi: 10.7554/eLife.59151
pii: 59151
pmc: PMC7438110
doi:
pii:
Substances chimiques
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Banques de données
Dryad
['10.5061/dryad.0p2ngf1xg']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : EB002026
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM080189
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA074305
Pays : United States
Organisme : NCI NIH HHS
ID : CA74305
Pays : United States
Organisme : American Heart Association
ID : 19POST34380800
Pays : International
Organisme : Austrian Science Fund FWF
ID : J 3872
Pays : Austria
Informations de copyright
© 2020, Chu et al.
Déclaration de conflit d'intérêts
NC, TV, HB, AS, AB, HA No competing interests declared, PC Senior editor, eLife
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