title: Sequence- and interactome-based prediction of viral protein hotspots targeting host proteins: a case study for HIV Nef.
abstract: Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk.
authors: Center for Integrated Bioinformatics, School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, United States of America.
authors: Mahdi
authors: M
authors: Sarmady
authors: William
authors: W
authors: Dampier
authors: Aydin
authors: A
authors: Tozeren
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D015234:HLA-A Antigens / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000737:chemistry / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck / Q000737:chemistry / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000737:chemistry / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D015234:HLA-A Antigens; D009363:Neoplasm Proteins; D051567:Proto-Oncogene Proteins c-vav; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C496618:VAV1 protein, human; D054311:nef Gene Products, Human Immunodeficiency Virus; C494957:FYN protein, human; C496631:HCK protein, human; D051076:Proto-Oncogene Proteins c-fyn; D051572:Proto-Oncogene Proteins c-hck; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D019204:GTP-Binding Proteins