title: Structural insight into GRIP1-PDZ6 in Alzheimer's disease: study from protein expression data to molecular dynamics simulations.
abstract: Protein-protein interaction domain, PDZ, plays a critical role in efficient synaptic transmission in brain. Dysfunction of synaptic transmission is thought to be the underlying basis of many neuropsychiatric and neurodegenerative disorders including Alzheimer's disease (AD). In this study, Glutamate Receptor Interacting Protein1 (GRIP1) was identified as one of the most important differentially expressed, topologically significant proteins in the protein-protein interaction network. To date, very few studies have analyzed the detailed structural basis of PDZ-mediated protein interaction of GRIP1. In order to gain better understanding of structural and dynamic basis of these interactions, we employed molecular dynamics (MD) simulations of GRIP1-PDZ6 dimer bound with Liprin-alpha and GRIP1-PDZ6 dimer alone each with 100 ns simulations. The analyses of MD simulations of Liprin-alpha bound GRIP1-PDZ6 dimer show considerable conformational differences than that of peptide-free dimer in terms of SASA, hydrogen bonding patterns, and along principal component 1 (PC1). Our study also furnishes insight into the structural attunement of the PDZ6 domains of Liprin-alpha bound GRIP1 that is attributed by significant shift of the Liprin-alpha recognition helix in the simulated peptide-bound dimer compared to the crystal structure and simulated peptide-free dimer. It is evident that PDZ6 domains of peptide-bound dimer show differential movements along PC1 than that of peptide-free dimers. Thus, Liprin-alpha also serves an important role in conferring conformational changes along the dimeric interface of the peptide-bound dimer. Results reported here provide information that may lead to novel therapeutic approaches in AD.
authors.affiliation: a Department of Biophysics , Bose Institute , Acharya J.C. Bose Centenary Building, P-1/12 C.I.T Scheme VII M, Kolkata 700054 , India.
authors.forename: Paulami
authors.initials: P
authors.lastname: Chatterjee
authors.affiliation: a Department of Biophysics , Bose Institute , Acharya J.C. Bose Centenary Building, P-1/12 C.I.T Scheme VII M, Kolkata 700054 , India.
authors.forename: Debjani
authors.initials: D
authors.lastname: Roy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D015870:Gene Expression; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054731:PDZ Domains; D025341:Principal Component Analysis; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D025941:Protein Interaction Mapping; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C491310:GRIP1 protein, human; D009419:Nerve Tissue Proteins; C094398:PPFIA1 protein, human
keywords: Alzheimer’s disease; GRIP1; MD simulation; PDZ domain; protein expression data