Viruses in the News

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RCDL 2006 Suzdal Oct 17-19 1

A Prototype of the HumanVirus Interact ome Resource (HVIR)

Tax1 Binds toBinds to Protein B

Interacts with Interacts with Co-Co-localizes withlocalizes with Co-Co-purifies withpurifies with

Forms a complex with Forms a complex with

“ ’’

Alex Pothen M. Zubair Kurt Maly

Chris Osgood John

Semmes

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Viruses in the News

• HIV, SARS, Avian Flu, Human flu pandemics

• A virus conjectured to be cause of

mammalian extinctions in the Pleistocene

• Viral proteins interacting with human

proteins are responsible for infection and transmission; targets for therapies

• Currently no automated tools to mine

published viral-human protein interactions

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Coping with Growing Proteomic Information

• Recent advances in protein science

– High throughput experimental methodologies: Yeast 2-hybrid system, Tagged affinity purification, etc.

• On-line literature and protein interactions

databases growing rapidly (>16 Million abstracts in PubMed)

• Need for automated tools to aggregate data, process it, and present it visually in biologically meaningful ways

• Need standards for representing data, and tools that support interoperable databases

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The HVIR Framework

• Viral-human protein interactions mined from the literature, e.g., PubMed

• Human interactome from curated databases, e.g., Human Protein Reference Database (HPRD)

• Integrate the data into a repository, HVIR

– Standards for representing protein interactions – Unique IDs from International Protein Index

– Semi-automated curation

– Regularly harvest new data from literature, databases – Build tools to be interoperable

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The HVIR Framework

• Organize interactions network in biologically meaningful ways

• Visualize the network for interactive exploration

• Make biological inferences, guide further expts.

• Initially create this tool for the Human T-cell Lukemia virus (HTLV-1), its protein, Tax

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Four Objectives of HVIR

• Tools for creating and sharing protein interaction data

• Tools for processing and organizing interaction networks

• Tools for validating interactions

• Tools for evaluating effectiveness and

scalability of the tools above

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Four Objectives of HVIR

• Creating and sharing interactions: literature

mining, standards for representing interactions data, protocols for harvesting data from multiple databases (Open Architecture Initiative)

• Processing interactome networks: clustering using multiple criteria, visualization tools for exploring networks

• Validating content: assign confidence values

using probabilistic models, curate ones with low confidence

• Evaluate effectiveness: focus groups of users evaluate how HVIR guides experimentation

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Identifying proteins in Tax complex (Durkin, Semmes)

S-Tax-G FP

kDa 250160 105 75 50

35

30

S-Tax-GFP S-G

FP

PR04-231 (DNA-PK)

PR04-189 PR04-191 PR04-192 PR04-193

PR04-194

PR04-195 PR04-196

kDa 160 105 75 50

35

30 250

PR04-190

S-GFP S-Tax-GFP

S-Tax-GFP

S-GFP

A B

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Tax co-localizes with activated DNA-PK (Durkin, Semmes)

STaxGFP Nuclear stain

DNA-PK

p-T2609 merge

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Summary of Work

• Designed HVIR to provide virologists with data on protein interaction networks

• Four major sets of tools: creating interaction data, processing it, validating it, and

evaluating effectiveness.

• Built a prototype for the HTLV-1 virus in collaboration with virologists and

demonstrated it to them.

• The Tax interactome now known to include 82 proteins vs. 8 when we began.

• Seeking funding to build and extend HVIR.

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Future work

• Detailed study of the Tax interactome to

generate predictions and validate utility of HVIR.

• Build HVIR and make it available for use by biologists.

• Employ a second virus, cytomegalovirus (CMV), with a larger set of proteins to study scalability (Julie Kerry, EVMS).

• Promote standards for data representation and interoperable protocols for data harvesting.

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HVIR Input form

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Tax interactors

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Second neighbors of Tax

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Local network of selected protein

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FR Layout, selected proteins

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A subnetwork of selected proteins

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A subnetwork of sel. proteins

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Incremental Navigation

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Incremental Navigation

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Shortest path from Tax

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Zooming in on a subnetwork

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Current version of Tax network

N = 82