ISMB 2005 Detroit, June 27 th 2005 Proteome 1 Michal Linial Institute of Life Sciences The Hebrew University Jerusalem, Israel Computer Science and Engineering.

ISMB 2005Detroit, June 27th 2005

Proteome 1

Michal LinialInstitute of Life SciencesThe Hebrew UniversityJerusalem, Israel

Computer Science and EngineeringUniversity of Washington, Seattle

•The term proteome, coined in 1994. A linguistic equivalent to the concept of genome

Proteome - complete set of proteins that is expressed, and modified by the entire genome in the lifetime of a cell.

Practical: the complement of proteins expressed by a cell at any one time.

Proteome – by the dictionary

Proteomics (Practical) - the study of the proteome using technologies of large-scale protein separation and identification.

Large scale separation : 2DE Liquid Chromatography

Identification : MALDI MS Tandem MS/MS FT-MS …..

Proteomics – by the dictionary

Still to do: Imaging, Standardization, S/N…

Proteomics by Medline maturation of a field

1730

From 220 publications in the previous millennium (‘94-’99)To 21,350 (!!!) publications in this millennium (‘00-’05)

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1997 1998 1999 2000 2001 2002 2003 2004

Papers

Reviews

Proteomics –by Google the ultimate truth..

Proteomics 886,000 hits (2004) 4,700,000 hits (2005)

Genomics 2,070,000 hits (2004) 16,000,000 hits (2005)

Proteomics – in view of other fields

Proteome

Proteomics

Proteome

Proteomics

Genome

Genomics

Genome

GenomicsStructural proteome

Structural proteome

Database

Application

Database

ApplicationMolecular evolution

Molecular evolution

DataMining

DataMining

Chemistry

Cell Biology

Imaging

Biotechnology

Nanotechnology

Protein Science

Biochemistry

Proteomics –GenomicsSome fundamental differences

Genome Genomicsanalysis

proteome Proteomeanalysis

DNANc-RNA

mRNA Coding DNA ProteinsPeptidesGlyco, other modifications

linear DynamicUp/down

3D DynamicUp/ downvariants

CompletionArchived(EST, cDNA, GEO

No notion of completion

Poorly archived

Encoded information

Partially encoded

Proteomics – GenomicsEven more different…

Gene/ RNAdynamic

Proteindynamic

Stable molecules

Handling cheap/ easyMinimal modification Works in isolation

Fragile molecules

Handling dependentLabile modificationProtein-interactionLocalization dependent

Handle

Tech

HTP

Sequencing (established) MS related (not yet)

DNA array / genotyping/ expression / CGH/

Protein Chip (not yet)Antibodies array (not yet)

PCR – amplification

PCR – amplification

No PCR equivalent

No PCR equivalent

Protein Function is Context dependent

Protein sequence is fully identified Still we do not know the:Structural details ????????

Localization ????????

Interaction -small molecules ?????????

Interaction - protein partners ?????????

Types / dynamics of modifications ?????????

Life time ?????????

Challenge Isequence, structure and function

Structure space

Function space

20,000

30,000(function by GO)

Sequence space

2,000,000

Challenge II the building blocks

Domain Boundaries??Domain Interaction ??Domain and Function ??

Challenge III the modification

PTM identification??PTM modeling, dependency ??PTM and interaction ??

Challenge IV MS - measurements

Signal to noise ??Quantification ??Organelle proteomics ??Scoring and AccuracyEfficient searching

Challenge V P2P

Accuracy, FP ??Pathway and Networks ??Context dependency ??Network robustness ??

Expectation I: Clever protein chemistry(sophisticated protein chemists/ biochemist)

Differential labeling (comparative study)

Affinity labeling – improved purification

Improved quantification

Expectation II: Better Imaging(sophisticated optics, coloring, recording, analyses)

Impact of Proteomics on Human Health

Proteomic as diagnostic tool

Proteomics of disease (plasma , urine, CSF)

Proteomics for pathogen

ID proteomics (cancer, stem cells..)

Drug impact (metabolic, disease progression)

Diagnostic Protein Chip, Modification chip

Why bother…

Example

GABA - the major inhibitory NT in the brain

GABA related to Anxiety, mood disorder, epilepsy, Parkinson, Sleep…

Controlling the level of GABA response

How?

P2PA patch

of receptors

P2PA patch

of receptors

LocalizationA pool

of receptors

LocalizationA pool

of receptors

SignalingPhospho.

Endocytosis

SignalingPhospho.

Endocytosis

PTMUbiquitinationof receptors

PTMUbiquitinationof receptors

Life timeProteosome

action

Life timeProteosome

action

No signal at the genome/ transcriptome

levels

Proteome –ISMB Summary

…and another sign of maturation

2004: 31 submission (only 16 full papers)

2005: 46 submission (Structure, Pathways - not included)

MS and 2D related analysis 10 Protein-interaction 9 Protein Prediction Analysis 8 Seq to function Annotation 7 Specific Protein Families 5 Localization related 3 Others (modeling..) 4

What’s nextClassifying Noisy Data The Ig case Yu et alProtein Function Prediction- Kernels Borgwardt at alSubstrate Prediction – Caspase Garay-Malpartida et al******************************Transmembrane domains for classification Sdaka & LinialProtein-protein Interaction and NMR Mettu et al