Research Report 2010 - MDC

Project Management (GO-Bio)Dr. Annett BöddrichSigrid Schnögl*part of the period reportedAdministrative AssistantsErika PischSilke Spading*Several attempts have been made to systematicallymap PPI networks. However, it remains difficult toassess the quality and coverage of existing data sets. Incollaboration with the research group of Prof. MarcVidal from Harvard Medical School, Boston, we havedeveloped an approach to identify the most suitablequality parameters of currently available human interactomemaps. We found that high-throughput yeasttwo-hybrid (HT-Y2H) screening yields more accurateinteraction data for human proteins than non-systematicstudies of small numbers of individual interactions.This suggests that HT-Y2H screening is a powerfulmethod to map a significant portion of the humaninteractome. We estimated that the human interactomecontains ~130,000 binary interactions, most ofwhich remain to be mapped by systematic screenings.High quality data and accurate estimates of interactionnumbers are crucial to establish the magnitude of thetask of comprehensively mapping the human interactome(Venkatesan et al., 2009).Constructing directed protein interaction networksfor activated EGF/Erk signalingEpidermal growth factor (EGF) signaling through extracellular-signalregulated kinases (Erks) is a complexprocess involving a series of protein-protein interactions(PPIs) that propagate information from the plasmamembrane to transcription factors. To obtain aglobal view of EGF/Erk signaling and to predict potentialmodulators, we created a network connecting 1126proteins via 2626 PPIs using automated yeast twohybrid(Y2H) interaction mating. From this interactionmap, a network of activated signaling was generatedusing a naïve Bayesian classifier, in which informationon shortest PPI paths from membrane receptors totranscription factors was exploited to predictinput/output relationships between interacting proteins.Analysis of the resulting network model revealedregulatory motifs typical for information processingsystems. Moreover, it allowed predictions of potentialmodulators of EGF/Erk signaling, which were validatedin mammalian cell-based assays. This generic experimentaland computational approach provides a frameworkfor elucidating causal connections between proteinsand facilitates the identification of factors modulatingthe flow of information in signaling networks(Vinayagam et al., 2009, submitted).Selected PublicationsEhrnhoefer, DE, Bieschke, J, Boeddrich, A, Herbst, M, Masino, L, Lurz, R,Engemann, S, Pastore, A, Wanker, EE. (2008) Redirecting aggregationpathways: small molecule-mediated conversion of amyloidogenicpolypeptides into unstructured, off-pathway oligomers. Nat Struct MolBiol. 15(6), 558-66.Zolghadr, K, Mortusewicz, O, Rothbauer, U, Kleinhans, R, Goehler, H,Wanker, EE, Cardoso, MC and Leonhardt, H. (2008) A fluorescent twohybrid(F2H) assay for direct visualization of protein interactions in livingcells. Mol Cell Proteomics 7(11), 2279-87.Chaurasia, G, Malhotra, S, Russ, J, Schnögl, S, Hänig, C, Wanker, E andFutschik, M. (2009) UniHI 4: New tools for query, analysis andvisualization of the human protein-protein interactome. Nucleic AcidsRes. 37(Database issue), D657-60.Venkatesan, K, Rual, .J-F Vazquez, A, Stelzl, U, Lemmens, I, Hirozane-Kishikawa, T, Hao, T, Zenkner, M, Xin, X, Goh, K-I, Yildirim, MA, Simonis, N,Heinzmann, K, Gebreab, F, Sahalie, JM, Cevik, S, Simon, C, de Smet, A-S,Dann, E, Smolyar, A, Vinayagam, A, Yu, H, Szeto, D, Borick. H, Dricot, A,Klitgord, N, Murray, RR, Lin, C, Lalowski, M, Timm, J, Rau, K, Boone, C, Braun,P, Cusick, ME, Roth, FP, Hill, DE, Tavernier, J, Wanker, EE, Barabási, A-L andVidal, M. (2009) An empirical framework for binary interactome mapping.Nat Methods. 6(1), 83-90.Palidwor, GA, Shcherbinin, S, Huska, MR, Rasko, T, Stelzl, U, Arumughan, A,Foulle, R, Porras, P, Sanchez-Pulido, L, Wanker, EE, and Andrade-Navarro,MA. (2009) Detection of alpha-rod repeats using a neural network andapplication to huntingtin. PLoS Comput Biol. 5(3):e1000304.Function and Dysfunction of the Nervous System 185