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PROTEIN INTERACTION NETWORK – INFERENCE TOOL DIVYA RAO CANDIDATE FOR MASTER OF SCIENCE IN BIOINFORMATICS ADVISOR: Dr. FILIPPO MENCZER CAPSTONE PROJECT PRESENTATION SCHOOL OF INFORMATICS - INDIANA UNIVERSITY April 20, 2006 Outline Outline Background PIN-IT Sample Results Future Work References Acknowledgements Slide 2 of 19 • • • • • • Background PIN-IT Sample Results Future Work References Acknowledgements April 20, 2006 Outline Background Definitions PIN-IT Results Future Work References Acknowledgements Slide 3 of 19 Definitions • Proteins are complex, highmolecular weight organic compounds • Protein interactions are associations between protein molecules • Examples: enzymes, hormones, transcription factors, antibodies, structural proteins April 20, 2006 Outline Background Experimental Approaches Experiments PIN-IT Results • Immunoprecipitation Future Work References Acknowledgements http://www.molecularstation.com/protein/immunoprecipitation/ Slide 4 of 19 April 20, 2006 Outline Background Experiments PIN-IT Results Future Work References Acknowledgements High Throughput Experiments • DNA sequence analysis – Homology & Orthology – Limited to proteins encoded by a single gene in one species or two or more genes in another a A b B Species 2 a Species 1 Slide 5 of 19 b Species 3 April 20, 2006 Yeast Two Hybrid Outline Background Experiments • Bait & prey • Transcription: DNA -> RNA • Two haploid yeasts • Benefit: PIN-IT Results Future Work References Acknowledgements – yeast can express genes from almost any species • Limitation: – Mutations – false positives – May not detect weak or rapid interactions Slide 6 of 19 http://www.biochem.arizona.edu/classes/bioc568/bioc568.htm April 20, 2006 Background Other Tools PIN-IT Results Future Work References Acknowledgements Slide 7 of 19 PRISM http://gordion.hpc.eng.ku.edu.tr/prism/tutorial.php#predictions.php Outline April 20, 2006 Background ADVICE Other Tools Slide 8 of 19 http://advice.i2r.a-star.edu.sg/doc/flowchart.gif April 20, 2006 Outline Background Motivation PIN-IT Results Future Work References Acknowledgements Slide 9 of 19 Motivation • Interaction maps can be used to reveal drug targets – BCL6 in humans causes B-cell non-Hodgkin lymphoma. In the fruitfly the BCL6 ortholog binds calcineurin phosphatases – Hubs vs. peripheral proteins April 20, 2006 Outline Background PIN-IT Results Future Work References Acknowledgements Slide 10 of 19 Protein Interaction Network Inference Tool • Infer protein-protein interactions – Known protein interactions – Protein similarity April 20, 2006 Outline Background PIN-IT Data Sources Results Future Work References Acknowledgements PIN-IT Data sources • Database of Interacting Proteins (DIP) • Biomolecular Interaction Network Database (BIND) • Proteins with GI numbers, Taxon ID & experimental source • False positive rate – Immunoprecipitation, r = 0.1 – Yeast Two Hybrid, r = 0.6 Slide 11 of 19 April 20, 2006 PIN-IT Data Outline Background PIN-IT Data Number of proteins Number of Interactions Number of Organisms Slide 12 of 19 DIP BIND PIN-IT 18826 27809 43573 54172 44354 94659 109 1020 1033 April 20, 2006 Outline Background PIN-IT BLAST Results Future Work References Acknowledgements BLAST • Basic Local Alignment Search Tool ..AGTTAC.. I II I ..ACTTAG.. • Smith-Waterman algorithm • E-value – # of different alignments with scores equivalent to or better than S that are expected to occur in a database by chance • Orthologus proteins • BLASTP Slide 13 of 19 April 20, 2006 Calculating Inference I B A S y D x I ( A, B ) 1 rexp( A, B ) Where: S ( A , x ) E( A , x ) n r is the false positive rate D( x , y ) S ( A, x ) I ( A, B ) S ( B , y ) E is the e-value from BLAST n is the size of the dataset suggest( a , b ) arg m ax D( a ,b ) ( a ,b ) Slide 14 of 19 April 20, 2006 Outline Background Demo PIN-IT Demo Results • PIN-IT Future Work References Acknowledgments Slide 15 of 19 April 20, 2006 Results Outline Background PIN-IT Results Future Work Putative integral membrane E3 ubiquitin ligase Interacts with mRNAs encoding membraneassociated proteins References Acknowledgements Slide 16 of 19 6324320 6322550 6321260 6323766 Has roles in maintenance of cell wall integrity Putative integral membrane, negative regulation of amino acid uptake April 20, 2006 Outline Background Future Work PIN-IT Results Future Work References Acknowledgements Slide 17 of 19 • Allow for the user to upload their protein sequences and interactions • Better estimation of experimental false positive rates • Work with biologists to validate the tool and fine-tune the parameters April 20, 2006 References Outline Background PIN-IT • • Results Future Work • References • Acknowledgements • • • • • • • • Slide 18 of 19 Campbell, M. A., Heyer, L.A. Discovering Genomics, Proteomics & Bioinformatics. India: Pearson Education, 2004, pp176-183. Ito T, et al.: "A comprehensive two-hybrid analysis to explore the yeast protein interactome,". Proc Natl Acad Sci 2001, 98:4569-74. Titz B, et al.: "What do we learn from high-throughput protein interaction data?". Expert Rev Proteomics 2004, 1:111-21. Giot L, et al.: "A protein interaction map of Drosophila melanogaster,". Science 2003 302: 1727-1736 Aytuna,A.S, Gursoy,A. Keskin,O., (2005). Prediction of protein-protein interactions by combining structure and sequence conservation in protein interfaces. Bioinformatics 21(12):2850-2855 Tan, Soon-Heng, Zhang, Zhuo, Ng, See-Kiong ADVICE: Automated Detection and Validation of Interaction by CoEvolution Nucl. Acids Res. 2004 32: W69-72 Protein Interactions by Structural Matching (PRISM): http://gordion.hpc.eng.ku.edu.tr/prism/index.php Automated Detection and Validation of Interaction by Co-Evolution (ADVICE): http://advice.i2r.a-star.edu.sg/ DIP: http://dip.doe-mbi.ucla.edu/ BIND: http://www.bind.ca/Action Immunoprecipitation Image: http://www.molecularstation.com/protein/immunoprecipitation/ Yeast Two Hybrid system image: http://www.biochem.arizona.edu/classes/bioc568/bioc568.htm April 20, 2006 Outline Acknowledgements Background PIN-IT Results Future Work References Acknowledgements Slide 19 of 19 • • • • • • • Dr. Filippo Menczer Dr. Haixu Tang Dr. Alessandro Flammini Dr. Sun Kim Dr. Mehmet Dalkilic Dr. Gary Wiggins Linda Hostetter April 20, 2006 Query April 20, 2006 Query Results April 20, 2006 Node Information Query Results April 20, 2006 Interaction Edge Information April 20, 2006 Query Results April 20, 2006 Similarity Edge Information April 20, 2006 Query Results April 20, 2006 Inference Edge Information April 20, 2006