title: Investigation of binding phenomenon of NSP3 and p130Cas mutants and their effect on cell signalling.
abstract: Members of the novel SH2-containing protein (NSP3) and Crk-associated substrate (p130Cas) protein families form a multi-domain signalling platforms that mediate cell signalling process. We analysed the damaging consequences of three mutations, each from NSP3 (NSP3(L469R), NSP3(L623E), NSP3(R627E)) and p130Cas (p130Cas(F794R), p130Cas(L787E), p130Cas(D797R)) protein with respect to their native biological partners. Mutations depicted notable loss in interaction affinity towards their corresponding biological partners. NSP3(L469R) and p130Cas(D797R) mutations were predicted as most prominent in docking analysis. Molecular dynamics (MD) studies were conducted to evaluate structural consequences of most prominent mutation in NSP3 and p130Cas obtained from the docking analysis. MD analysis confirmed that mutation in NSP3(L469R) and p130Cas(D797R) showed significant structural deviation, changes in conformations and increased flexibility, which in turn affected the binding affinity with their biological partners. Moreover, the root mean square fluctuation has indicated a rise in fluctuation of residues involved in moderate interaction acquired between the NSP3 and p130Cas. It has significantly affected the binding interaction in mutant complexes. The results obtained in this work present a detailed overview of molecular mechanisms involved in the loss of cell signalling associated with NSP3 and p130Cas protein.
authors.affiliation: Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore, 632014, Tamil Nadu, India.
authors.lastname: Balu K
authors.forename: Vidya
authors.initials: V
authors.lastname: Rajendran
authors.forename: Rao
authors.initials: R
authors.lastname: Sethumadhavan
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
mesh_terms: D050719:Crk-Associated Substrate Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D050719:Crk-Associated Substrate Protein