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Proteome and Interactome Bioinformatics Proteome and interactome [email protected] Contents Protein-protein interactions Two-hybrid assays Mass spectrometry Cellular localization of proteins GFP tags Protein-DNA interactions ChIP-on-chip Functional genomics Two-hybrid assays [email protected] Two-hybrid method Transcription factor RNA DNA-binding Activation pol Hybrid constructions Bait Prey DNA-binding ORF A ORF B Activation A B Interaction No interaction → reporter gene is expressed → reporter gene is not expressed Prey B Prey B RNA RNA pol Bait A pol Bait A Two-hybrid Uetz et al. (2000). Nature 403: 623-631 Ito et al. (2001) PNAS 98: 4569-4574 Comparison of the results When the second “comprehensive” Ito et al. (2001) PNAS analysis was published, the overlap 98: 4569- between thee results obtained in the 4574 two independent studies was surprisingly low. How to interpret this ? Problem of coverage ? Each study would only represent a fraction of what remains to be discovered. Problem of noise ? Either or both studies might contain a large number of false positives. Differences in experimental conditions ? Connectivity in protein interaction networks Jeong et al (2001) calculate connectivity in the protein interaction network revealed by the two-hybrid analysis of Uetz and co- workers. The connectivity follows a power law: most proteins have a few connections; a few proteins are highly connected Highly connected proteins correspond to essential proteins. Jeong, H., S.P. Mason, A.L. Barabasi, and Z.N. Oltvai. 2001. Lethality and centrality in protein networks. Nature 411: 41-42. Functional genomics Mass-spectrometry [email protected] Isolation of protein complexes 1. Construction of a bank of tag Y ORF TAG-fused ORFs 2. Expression of the Y tagged bait tagged baits in yeast + All cellular proteins,… 3. Cell lysis 4. Affinity purification anti-tag C epitope Y B D A E Other proteins,… Slide from Nicolas Simonis Mass spectrometry - Protein identification C Y B B A E Y D A 1 dimension SDS-PAGE E D C isolation B E C Mass spectrometry A = YPR184w B = YLR258w D = YKL085w C = YER133w Y = YPR160w E = YER054c Slide from Nicolas Simonis Protein complexes Gavin et al. (1999). Nature 415: 141-147 Tandem Affinity Purification (TAP) CELLZOME: 232 complexes Ho et al. (1999). Nature 415: 180-183 High-throughput mass-spectrometric protein complex identification (HMS-PCI) MDS proteomics 493 complexes Network of complexes Gavin et al. (1999). Nature 415: 141-147 Functional genomics Assessment of interactome data [email protected] Assessment of interactome data von Mering et al (2002). Nature. Comparison of large-scale interaction data von Mering et al (2002) compared the results from Two-hybrid assays Mass spectrometry (TAP and HMS-PCI) Co-expression in microarray experiments Synthetic lethality Comparative genomics (conservation of operons, phylogenetic profiles, and gene fusion) Among 80,000 interactions, no more than 2,400 are supported by two different methods. Each method is more specifically related to some functional classes cellular location Reference: von Mering et al. (2002). Nature 750 Comparison of pairs of interacting proteins with functional classes von Mering et al (2002). Nature 750. Validation with annotated complexes von Mering et al (2002) collected information on experimentally proven physical protein-protein interactions, and measured the coverage and positive predictive value of each predictive method Coverage • fraction of reference set covered by the data. Positive predictive value • Fraction of data confirmed by reference set. • (Note: they call this “accuracy”, but this term is usually not used in this way) Beware: the scale is logarithmic ! This enforces the differences in the lower part of the percentages (0-10), but “compresses” the values between 10 and 50, which gives a false impression of good accuracy. von Mering et al (2002). Nature. Bioinformatics Cellular localization of proteins [email protected] Nature (2003) 425: 686-691 4156 proteins detected by fluorescence microscopy analysis Slide adapted from Bruno André Global analysis of protein localization This analysis allowed to obtain information for thousands of proteins for which the cellular localization was previously unknown. Slide adapted from Bruno André Localisation and ORF function For historical reasons, the yeast genome is “over-annotated”. The method used for predicting genes from genome sequences included many false positives, especially among short predicted ORFs. Most of the questionable ORFs were unobserved in the global localization analysis. These mainly correspond to short ORFs. Source: Bruno André Functional genomics Protein-DNA interactions ChIP-on-chip technology [email protected] The ChIP-on-chip method Chromatin Immuno-precipitation (ChIP) Tagging of a transcription factor of interest with a protein fragment recognized by some antibody. Immobilization of protein-DNA interactions with a fixative agent. DNA fragmentation by ultrasonication. Precipitation of the DNA-protein complexes. Un-binding of the DNA-protein bounds. Measurement of DNA enrichment. Two extracts are co-hybridized on a microarray (chip),where each spot contains one DNA fragment where a factor is likely to bind (e.g. an intergenic region, or a smaller fragment).. • For the yeast S.cerevisiae, chips have been designed with all the intergenic regions (6000 regions, avg. 500bp/region) • Recent technology allows to spot 3e+5 300bp DNA fragments on a single slide. The first extract (labelled in red) is enriched in DNA fragments bound to the tagged transcription factor. The second extract (labelled in green) has not been enriched. The log-ratio between red and green channels indicate the enrichment for each intergenic region. Lee et al (2002) In 2002, Lee et al publish a systematic characterization of the binding regions of 106 yeast transcription factors. Lee et al. 2002. Science 298: 799-804..
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