Mechanisms of isoform-specific residue influence on GTP-bound HRas, KRas, and NRas.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
04 10 2022
04 10 2022
Historique:
received:
03
03
2022
revised:
04
05
2022
accepted:
01
07
2022
pubmed:
8
7
2022
medline:
12
10
2022
entrez:
7
7
2022
Statut:
ppublish
Résumé
HRas, KRas, and NRas are GTPases with a common set of effectors that control many cell-signaling pathways, including proliferation through Raf kinase. Their G-domains are nearly identical in sequence, with a few isoform-specific residues that have an effect on dynamics and biochemical properties. Here, we use accelerated molecular dynamics (aMD) simulations consistent with solution x-ray scattering experiments to elucidate mechanisms through which isoform-specific residues associated with each Ras isoform affects functionally important regions connected to the active site. HRas-specific residues cluster in loop 8 to stabilize the nucleotide-binding pocket, while NRas-specific residues on helix 3 directly affect the conformations of switch I and switch II. KRas, the most globally flexible of the isoforms, shows greatest fluctuations in the switch regions enhanced by a KRas-specific residue in loop 7 and a highly dynamic loop 8 region. The analysis of isoform-specific residue effects on Ras proteins is supported by NMR experiments and is consistent with previously published biochemical data.
Identifiants
pubmed: 35794829
pii: S0006-3495(22)00551-3
doi: 10.1016/j.bpj.2022.07.005
pmc: PMC9617160
pii:
doi:
Substances chimiques
Nucleotides
0
Protein Isoforms
0
Guanosine Triphosphate
86-01-1
raf Kinases
EC 2.7.11.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3616-3629Informations de copyright
Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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