The Self-Association of the KRAS4b Protein is Altered by Lipid-Bilayer Composition and Electrostatics.
Angew Chem Int Ed Engl
; 62(18): e202218698, 2023 04 24.
Article
em En
| MEDLINE
| ID: mdl-36883374
ABSTRACT
KRAS is a peripheral membrane protein that regulates multiple signaling pathways, and is mutated in ≈30 % of cancers. Transient self-association of KRAS is essential for activation of the downstream effector RAF and oncogenicity. The presence of anionic phosphatidylserine (PS) lipids in the membrane was shown to promote KRAS self-assembly, however, the structural mechanisms remain elusive. Here, we employed nanodisc bilayers of defined lipid compositions, and probed the impact of PS concentration on KRAS self-association. Paramagnetic NMR experiments demonstrated the existence of two transient dimer conformations involving alternate electrostatic contacts between R135 and either D153 or E168 on the "α4/5-α4/5" interface, and revealed that lipid composition and salt modulate their dynamic equilibrium. These dimer interfaces were validated by charge-reversal mutants. This plasticity demonstrates how the dynamic KRAS dimerization interface responds to the environment, and likely extends to the assembly of other signaling complexes on the membrane.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas p21(ras)
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Bicamadas Lipídicas
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article