title: Biophysical aspect of phosphatidylinositol 3-kinase and role of oncogenic mutants (E542K & E545K).
abstract: Genetic variations in oncogenes can often promote uncontrolled cell proliferation by altering the structure of the encoded protein, thereby altering its function. The PI3KCA oncogene that encodes for p110α, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is one the most frequently mutated oncogenes in humans. PI3K plays a pivotal role in cell division. PI3K consists of two subunits: the catalytic (p110α) and regulatory (p85α). The regulatory subunit usually controls the catalytic subunit and switches off the enzyme when not required. It is believed that mutations in PI3KCA gene can alter the control of p85α over p110α and can sustain p110α in a prolonged active state. This in turn results in uncontrolled cell division. In this study, we investigate the pathogenic role of two point mutations: E542K and E545K on p110α subunit and how they alter its binding with the regulatory subunit. Molecular interaction and molecular dynamic simulation analysis are performed to study the dynamic behaviour of native and mutant structures at atomic level. Mutant p110α showed less interaction with its regulatory partner p85α than the native did, due to its expanded and rigid structure. Our analysis clearly points out that the structural and functional consequences of the mutations could promote tumour proliferation.
authors.affiliation: a Bioinformatics Division, School of Bio Sciences and Technology (SBST) , Vellore Institute of Technology University , Vellore 632014 , Tamil Nadu , India.
authors.forename: Namrata
authors.initials: N
authors.lastname: Kalsi
authors.affiliation: a Bioinformatics Division, School of Bio Sciences and Technology (SBST) , Vellore Institute of Technology University , Vellore 632014 , Tamil Nadu , India.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Gopalakrishnan
authors.affiliation: a Bioinformatics Division, School of Bio Sciences and Technology (SBST) , Vellore Institute of Technology University , Vellore 632014 , Tamil Nadu , India.
authors.forename: Vidya
authors.initials: V
authors.lastname: Rajendran
authors.affiliation: b Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology , Palampur , Himachal Pradesh , India.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D019869:Phosphatidylinositol 3-Kinases
keywords: PI3K; biological partner; molecular dynamics; regulatory partner