In-silico screening of cancer associated mutation on PLK1 protein and its structural consequences
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ORIGINAL PAPER
In-silico screening of cancer associated mutation on PLK1 protein and its structural consequences Balu Kamaraj & Vidya Rajendran & Rao Sethumadhavan & Rituraj Purohit
Received: 14 September 2013 / Accepted: 21 October 2013 / Published online: 23 November 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract The Polo-like kinases (Plks) are a conserved subfamily of serine-threonine protein kinases that have significant roles in cell proliferation. The serine/threonine protein kinases or polo-like kinase 1 (PLK1) exist in centrosome during interphase and is an important regulatory enzyme in cell cycle progression during M phase. Mutations in mammalian PLK1 were found to be over expressed in various human cancers and it is disrupting the binding ability of polo box domain with target peptide. In this analysis we implemented a computational approach to filter the most deleterious and cancer associated mutation on PLK1 protein. We found W414F as the most deleterious and cancer associated by Polyphen 2.0, SIFT, I-mutant 3.0, PANTHER, PhD-SNP, SNP&GO, Mutpred and Dr Cancer tools. Molecular docking and molecular dynamics simulation (MDS) approach was used to investigate the structural and functional behavior of PLK1 protein upon mutation. MDS and docking results showed stability loss in mutant PLK1 protein. Due to mutation, PLK1 protein became more flexible and alters the dynamic property of protein which might affect the interaction with target peptide and leads to cell proliferation. Our study provided a well designed computational methodology to examine the cancer associated nsSNPs and their molecular mechanism. It further helps scientists to develop a drug therapy against PLK1 cancerassociated diseases.
Balu Kamaraj and Vidya Rajendran equally contributed to this paper. B. Kamaraj : V. Rajendran : R. Sethumadhavan : R. Purohit (*) School of Bio Sciences and Technology (SBST), Bioinformatics Division, Vellore Institute of Technology University, Vellore 632014, Tamil Nadu, India e-mail: [email protected] R. Purohit Human Genetics Foundation, Torino, Via Nizza 52, 10126 Torino, Italy
Keywords Flexibility . Molecular dynamics simulations . PLK-1 protein
Introduction The polo-like kinases (Plks) are a conserved subfamily of serine-threonine protein kinases that have significant roles in cell proliferation [1, 2]. In mammals, the multiple forms of plks are designated as PLK1, PLK-2/Snk, PLK-2/Prk/Fnk, and PLK/Sak. Among the Plks, PLK1 has been studied most extensively because of its ability to override cellular checkpoints and induce genetic instability, which leads to oncogenic transformation of human cells [3, 4]. PLK1 protein is composed of a common N-terminal catalytic domain and Cterminal regulatory domain with highly conserved sequences named polo boxes (PB). The polo box domain (PBD) is observed only in the PLK and contains a characteristic sequence, which is the trademark of this protein family. This domain is supposed to be involved in an auto regulatory mechanism or in targeting the kinas
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