title: Impact of point mutation P29S in RAC1 on tumorigenesis.
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.
authors.affiliation: Computational Biology Lab, Department of Biotechnology, Vellore Institute of Technology University, Vellore, Tamil Nadu, 632014, India.
authors.forename: Vidya
authors.initials: V
authors.lastname: Rajendran
authors.affiliation: Computational Biology Lab, Department of Biotechnology, Vellore Institute of Technology University, Vellore, Tamil Nadu, 632014, India.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Gopalakrishnan
authors.affiliation: Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India. riturajpurohit@gmail.com.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D011487:Protein Conformation; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D020830:rac1 GTP-Binding Protein
keywords: Docking; Interaction energy; Molecular dynamics; Regulatory partner