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Impact of point mutation P29S in RAC1 on tumorigenesis
Vidya Rajendran1, Chandrasekhar Gopalakrishnan1, Rituraj Purohit2
1Computational Biology Lab, Department of Biotechnology, Vellore Institute of Technology University, Vellore, Tamil Nadu, 632014, India.
Abstract:
A point mutation (P29S) in the RAS-related C3 botulinum toxin substrate 1 (RAC1) was considered to be a trigger for melanoma, a form of skin cancer with highest mortality rate. In this study, we have investigated the pathogenic role of P29S based on the conformational behavior of RAC1 protein toward guanosine triphosphate (GTP). Molecular interaction, molecular dynamics trajectory analysis (RMSD, RMSF, Rg, SASA, DSSP, and PCA), and shape analysis of binding pocket were performed to analyze the interaction energy and the dynamic behavior of native and mutant RAC1 at the atomic level. Due to this mutation, the RAC1 switch I region acquired more flexibility and, to compensate it, the switch II region becomes rigid in their conformational space, as a result of which the interaction energy of the protein for GTP increased. The overall results strongly implied that the changes in atomic conformation of the switch I and II regions in mutant RAC1 protein were a significant reason for its malignant transformation and tumorigenesis. We raised the opportunity for researchers to design possible therapeutic molecule by considering our findings.
Insights
A specific mutation in the RAS-related C3 botulinum toxin substrate 1 (RAC1) protein may drive melanoma development. This RAC1 P29S mutation alters protein structure, increasing its affinity for GTP and promoting skin cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Melanoma, a deadly skin cancer, may be triggered by mutations.
- The RAS-related C3 botulinum toxin substrate 1 (RAC1) protein plays a role in cell signaling.
Purpose of the Study:
- To investigate the pathogenic role of the RAC1 P29S mutation.
- To analyze the conformational changes in RAC1 upon GTP binding.
Main Methods:
- Molecular dynamics simulations.
- Binding pocket shape analysis.
- Analysis of protein dynamics (RMSD, RMSF, Rg, SASA, DSSP, PCA).
Main Results:
- The P29S mutation caused increased flexibility in RAC1's switch I region and rigidity in its switch II region.
- Mutant RAC1 exhibited higher interaction energy with guanosine triphosphate (GTP).
- Conformational changes in switch regions were linked to malignant transformation.
Conclusions:
- The RAC1 P29S mutation contributes to melanoma pathogenesis by altering protein conformation and GTP binding.
- Findings offer insights for developing targeted melanoma therapies.
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