PROTEIN INTERACTION NETWORK – INFERENCE TOOL DIVYA RAO CANDIDATE FOR MASTER OF SCIENCE IN...

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

Outline Outline Background PIN-IT Sample Results Future Work References Acknowledgements

• Background• PIN-IT• Sample Results• Future Work• References• Acknowledgements

April 20, 2006

Slide 2 of 19

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

Slide 3 of 19

Experimental Approaches

• Immunoprecipitation

Outline Background

Experiments

PIN-IT Results Future Work References Acknowledgements

http://www.molecularstation.com/protein/immunoprecipitation/

April 20, 2006

Slide 4 of 19

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

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

Slide 6 of 19

http://www.biochem.arizona.edu/classes/bioc568/bioc568.htm

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

Slide 7 of 19

ADVICE BackgroundOther Tools

http://advice.i2r.a-star.edu.sg/doc/flowchart.gif April 20, 2006

Slide 8 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

Outline Background

Motivation PIN-IT Results Future Work References Acknowledgements

April 20, 2006

Slide 9 of 19

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

Slide 10 of 19

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

Slide 11 of 19


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

Slide 12 of 19

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


BLAST Results Future Work References Acknowledgements

April 20, 2006

Slide 13 of 19

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

Slide 14 of 19

Demo

• PIN-IT


Demo Results Future Work References Acknowledgments

April 20, 2006

Slide 15 of 19


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

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


April 20, 2006

Slide 17 of 19

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


April 20, 2006

Slide 18 of 19

Acknowledgements

• Dr. Filippo Menczer• Dr. Haixu Tang• Dr. Alessandro Flammini• Dr. Sun Kim• Dr. Mehmet Dalkilic• Dr. Gary Wiggins• Linda Hostetter


April 20, 2006

Slide 19 of 19

Query

April 20, 2006

April 20, 2006

Query Results

Node Information

April 20, 2006

Query Results

Interaction Edge Information

April 20, 2006

April 20, 2006

Query Results

Similarity Edge Information

April 20, 2006

April 20, 2006

Query Results

Inference Edge Information

April 20, 2006

PROTEIN INTERACTION NETWORK – INFERENCE TOOL DIVYA RAO CANDIDATE FOR MASTER OF SCIENCE IN...

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