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Decreased conformational stability in the oncogenic N92I mutant of Ras-related C3 botulinum toxin substrate 1.
- Source :
-
Science advances [Sci Adv] 2019 Aug 07; Vol. 5 (8), pp. eaax1595. Date of Electronic Publication: 2019 Aug 07 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Ras-related C3 botulinum toxin substrate 1 (Rac1) functions as a molecular switch by cycling between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. An oncogenic mutant of Rac1, an N92I mutant, strongly promotes cell proliferation and subsequent oncogenic activities by facilitating the intrinsic GDP dissociation in the inactive GDP-bound state. Here, we used solution nuclear magnetic resonance spectroscopy to investigate the activation mechanism of the N92I mutant. We found that the static structure of the GDP binding site is not markedly perturbed by the mutation, but the overall conformational stability decreases in the N92I mutant, which then facilitates GDP dissociation by lowering the activation energy for the dissociation reaction. On the basis of these results, we proposed the activation mechanism of the N92I mutant, in which the decreased conformational stability plays important roles in its activation process.
- Subjects :
- Binding Sites
Guanosine Diphosphate metabolism
Humans
Hydrogen Bonding
Kinetics
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Protein Conformation, alpha-Helical
Protein Stability
Protein Structure, Tertiary
Recombinant Proteins biosynthesis
Recombinant Proteins chemistry
Recombinant Proteins isolation & purification
Temperature
rac1 GTP-Binding Protein genetics
rac1 GTP-Binding Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 5
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 31457101
- Full Text :
- https://doi.org/10.1126/sciadv.aax1595