Introduction to biological networks

1. Introduction to biological networks

2. GENOME protein-gene interactions PROTEOME protein-protein interactions METABOLISM Bio-chemical reactions Citrate Cycle

3. Types of biological network • Genetic regulatory network • Protein-protein interaction network • Metabolic network • Signal transduction network

4. Gene Regulation Network Regulatory proteins Promoter 1 Promoter 2 Promoter 3

5. Transcription network activator repressor

6. Protein-Protein Interaction Network Saccharomyces cerevisiae Node: protein Edge: protein-protein interaction

7. Metabolic Network Metabolic Pathway Node: Chemicals or Proteins Edge: Chemical reaction

8. cAMP signaling transduction of Dictyostelium discoideum Dictyostelium discoideum

9. High throughput experiments to identify interaction in network

10. Experiments for Protein-Protein Interaction

11. Saccharomyces Cerevisiae Nature, 415, 180, (2001) Nature, 415, 141, (2001) HMS-PCI TAP tag Cellzome is a private Corporation in German

12. Helicobacter Pylori

13. Drosophila melanogaster Two hybrid Science, 5 Dec, 302, 1727, (2003)

14. Caenorhabditis elegans (Worm)

15. Experimetal Methods • HMS-PCI(High-throughput mass spectrometric protein complex identification) • TAP (Tandem Affinity Purification) • Yeast two hybrid • Immunoprecipitation • Phage display • Fluorescence resonance energy transfer (FRET)

16. TAP tag Purification TAP tag • TAP tag contains 1. two IgG binding domains of Staphylococcus aureus protein A (ProtA) 2. Calmodulin binding petide (CBP) 3. TEV protease cleavage site

18. TAP tag

19. Advantage: Detects in physiological condition, high-throughput • Disavantage: Tag may disturb protein interaction miss the protein complexes that are not present in such condition

20. HMS-PCI • High-throughput mass spectrometric protein complex indentification • Use epitope tag

21. Yeast Two Hybrid Method

22. Advantage : In vivo experiment, transient and unstable interactions could be detected • Disadvantage: many false positive, only two proteins were detected at a time it take place in the nucleus, so many protein interactions are not detected in their native environment

23. Immunoprecipitation

24. Advantages of this approach This approach can test  the protein associations in nature condition in the cell. The isolated proteins (or complex) can be used to do other functional assay.

25. Phage Display

26. Advanage: high throughput Can be used to elucidate nuclear protein interaction.

27. Fluorescence Resonance Energy Transfer (FRET) When the donor and acceptor come close to 10~100 , the donor will transmit energy to acceptor, we could monotor the protein interaction by fluorescence.

28. Protein-Protein Interaction Database • BIND: Biomolecular Interaction Network Database http://www.blueprint.org/bind/bind.php • DIP: Database of Interacting Protein • Genome Website: http://www.hgmp.mrc.ac.uk/GenomeWeb/

31. Yeast protein-protein interaction ☺About 80000 interactions between yeast proteins are available from high-throughput methods. ☺Only ~2400 interactions are supported by more than two methods. ☺Possible reasons are ® the methods may not have reached saturation ® many methods may produce false positives ® some methods has difficulties for certain types of interaction.

32. Assign 80000 interactions of 5400 yeast proteins a confidence value 11855 interactions with high and medium confidence among 2617 proteins

33. Biological significance of protein-protein interaction? • Assemble proteins together into protein complex • Bring the proteins(signaling proteins) to its activate or function place • Binding of one protein to another can induce conformational change that affect activity or accessibility of additional binding domain

34. Mad Myc Max Burkitt lymphoma neuroblastomas small cell lung cancers Promoter Gene Sequence

35. Clb Cln Sic1 Partner Specific Cdc28 YBR160W Cdc28 YBR160W Yeast cell cylce Cyclin-CDK (Cyclin-dependent kinases) complexes

36. Scaffold Protein Reactants E1 E2 Product E3 Reactants E1 E2 E3 Scaffold Reactants E1 E2 Protein complex Product E3

37. Experiments for genetic regulation interaction

38. Protein-DNA interaction Chromatin Inmmunoprecipitation (ChIP)

39. Science 298, 799, (2002).

40. Yeast cell cycle regulatory network

41. Mathematical modeling of biological networks as a graph

42. Protein-protein interaction network

43. Protein-protein interaction network Node: protein Edge: interaction

44. Protein-Protein Interaction Network Saccharomyces cerevisiae Node: protein Edge: protein-protein interaction

45. Metabolic network Substrates linked to all its products Node: protein or chemicals Edge: chemical reaction

46. Biochemical reduction Reduced graph representation Graph representation Pathway map

47. E. coli metabolic network with biochemical reduction

48. Topological reduction Remove hair nodes, and replacing arc with single link

49. E. coli metabolic network with topological reduction

50. Both protein-protein interaction network and metabolic network are modeling as undirected graphs.