Modeling cells with protein networks

1. Modeling cells with protein networks Trey Ideker University of California San Diego Department of Bioengineering

2. From protein sequences… to protein networks Query Sequence GACTGCATTAC Global query Database DNA and protein sequences Database / Scaffold of Molecular Interactions Conservedgenes/proteins Interaction pathway and complexesassociated with query data

3. Protein→DNA interactions Protein—protein interactions Biochemical reactions

4. Also like sequence, protein interaction data are exponentially growing… EMBL Database Growthtotal nucleotides (gigabases) DIP Database Growthtotal interactions 10 5 0 1980 1990 2000 (As are the false positives!!!)

5. Cross-comparison of networks: • Conserved regions in the presence vs. absence of stimulus • Conserved regions across different species Kelley et al. PNAS 2003 Kelley et al. NAR 2004 http://www.pathblast.org Sharan et al. RECOMB 2004

6. Multiple protein-protein network alignmentof three model eukaryotes (Sharan et al. PNAS 2005) • YEAST (Multiple publications-Uetz, Ito, Gavin, Ho) • 4,393 proteins, 14,584 interactions • WORM (Li et al. Science 303, 2004) • 2,719 proteins, 3,926 interactions • FLY (Giot et al. Science 302, 2003) • 7,048 proteins, 20,884 interactions Baker’s yeast (Saccharomyes cerevisiae) Fruit fly(Drosophila melanogaster) Nematode worm(Caenorhabditis elegans)

7. Example yeast/worm/fly alignments ?

8. 40-50% of predictions confirmed

9. Plasmodium: a network apart? Plasmodium-specificprotein complexes Conserved Plasmodium / Saccharomyces protein complexes Suthram et al. Nature 2005La Count et al. Nature 2005

10. Plasmodium has only 3 conserved complexes with yeast and none with other species # conserved complexes

11. Finding physical pathways to explain genetic interactions Genetic Interactions: • Classical method used to map pathways in model species • Highly analogous tomulti-genic interaction in human disease and combination therapy • Thousands are being uncovered through systematic studies Thus as with other types, the number of known genetic interactions is exponentially increasing… Adapted from Tong et al., Science 2001

12. Synthetic lethals are another type of interaction that are appearing in large numbers A B A DB DA B DA DB Adapted from Hartman, Garvik, and Hartwell, Science 2001

13. Interpretation of genetic interactions (Guarente T.I.G. 1990) a a A A B B w w Parallel Effects (Redundant or Additive) Sequential Effects (Additive) GOAL: Identify downstream physical pathways Single A or B mutations typically abolish their biochemical activities Single A or B mutations typically reduce their biochemical activities

14. Integration of genetic and physical interactions 160 between-pathway models 101 within-pathway models Num interactions:1,102 genetic933 physical Kelley and Ideker Nature Biotechnology (2005)

15. Systematic identification of 160 “parallel pathway” relationships in yeast

16. Global organization of genetic linkages between physical pathways (A-Z) Bridging genetic interactions Overlapping pathways

17. The vision:First build the scaffold, then add the details Ideker and Lauffenburger Trends in Biotech. (2003)