PROTEIN INTERACTION NETWORK – INFERENCE TOOL DIVYA RAO CANDIDATE FOR MASTER OF SCIENCE IN...
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PROTEIN INTERACTION NETWORK – INFERENCE TOOL
DIVYA RAOCANDIDATE FOR MASTER OF SCIENCE IN
BIOINFORMATICSADVISOR: Dr. FILIPPO MENCZER
CAPSTONE PROJECT PRESENTATIONSCHOOL OF INFORMATICS - INDIANA
UNIVERSITY April 20, 2006
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Outline Outline Background PIN-IT Sample Results Future Work References Acknowledgements
• Background• PIN-IT• Sample Results• Future Work• References• Acknowledgements
April 20, 2006
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Definitions
• Proteins are complex, high-molecular weight organic compounds
• Protein interactions are associations between protein molecules
• Examples: enzymes, hormones, transcription factors, antibodies, structural proteins
Outline Background
Definitions PIN-IT Results Future Work References Acknowledgements
April 20, 2006
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Experimental Approaches
• Immunoprecipitation
Outline Background
Experiments
PIN-IT Results Future Work References Acknowledgements
http://www.molecularstation.com/protein/immunoprecipitation/
April 20, 2006
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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
Outline Background
Experiments
PIN-IT Results Future Work References Acknowledgements
A a
Species 1
Species 2
April 20, 2006
Slide 5 of 19
a
b
B
bSpecies 3
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Yeast Two Hybrid
• Bait & prey • Transcription:
DNA -> RNA• Two haploid
yeasts• Benefit:
– yeast can express genes from almost any species
• Limitation: – Mutations –
false positives– May not
detect weak or rapid interactions
Outline Background
Experiments PIN-IT Results Future Work References Acknowledgements
http://www.biochem.arizona.edu/classes/bioc568/bioc568.htm April 20, 2006
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PRISM Outline Background
Other Tools PIN-IT Results Future Work References Acknowledgements
http
://go
rdio
n.hp
c.en
g.ku
.edu
.tr/p
rism
/tuto
rial.p
hp#p
redi
ctio
ns.p
hp
April 20, 2006
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ADVICE BackgroundOther Tools
http://advice.i2r.a-star.edu.sg/doc/flowchart.gif April 20, 2006
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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
Outline Background
Motivation PIN-IT Results Future Work References Acknowledgements
April 20, 2006
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Protein Interaction Network Inference Tool
• Infer protein-protein interactions– Known protein interactions– Protein similarity
Outline Background PIN-IT Results Future Work References Acknowledgements
April 20, 2006
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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
Outline Background PIN-IT
Data Sources
Results Future Work References Acknowledgements
April 20, 2006
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Outline Background PIN-IT
Data
DIP BIND PIN-IT
Number of proteins 18826 27809 43573
Number of Interactions 54172 44354 94659
Number of Organisms 109 1020 1033
PIN-IT Data
April 20, 2006
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BLAST• Basic Local Alignment Search Tool
..AGTTAC.. I I I 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
Outline Background PIN-IT
BLAST Results Future Work References Acknowledgements
April 20, 2006
Slide 13 of 19
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Calculating Inference
AIB
xy
S
D
),(),(
),(),(),(),(
),(),(
),exp(),(
maxarg),(
1
baba
yBBAxAyx
xAxA
BABA
Dbasuggest
SISD
nES
rI
Where:
r is the false positive rate
E is the e-value from BLAST
n is the size of the dataset
April 20, 2006
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Demo
• PIN-IT
Outline Background PIN-IT
Demo Results Future Work References Acknowledgments
April 20, 2006
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Outline Background PIN-IT Results Future Work References Acknowledgements
April 20, 2006
Slide 16 of 19
Results
63225506324320
63237666321260
Interacts with mRNAs encoding membrane-associated proteins
Putative integral membrane E3 ubiquitin ligase
Putative integral membrane, negative
regulation of amino acid uptake
Has roles in maintenance of cell wall integrity
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Future Work
• 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
Outline Background PIN-IT Results Future Work References Acknowledgements
April 20, 2006
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References• 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-KiongADVICE: Automated Detection and Validation of Interaction by Co-EvolutionNucl. 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
Outline Background PIN-IT Results Future Work References Acknowledgements
April 20, 2006
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Acknowledgements
• Dr. Filippo Menczer• Dr. Haixu Tang• Dr. Alessandro Flammini• Dr. Sun Kim• Dr. Mehmet Dalkilic• Dr. Gary Wiggins• Linda Hostetter
Outline Background PIN-IT Results Future Work References Acknowledgements
April 20, 2006
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Query
April 20, 2006
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April 20, 2006
Query Results
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Node Information
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April 20, 2006
Query Results
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Interaction Edge Information
April 20, 2006
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April 20, 2006
Query Results
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Similarity Edge Information
April 20, 2006
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April 20, 2006
Query Results
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Inference Edge Information
April 20, 2006