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

The term proteome, coined in 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)

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 Genomics Structural proteome Structural proteome Database Application Database Application Molecular evolution Molecular evolution Data Mining Data Mining Chemistry Cell Biology Imaging Biotechnology Nanotechnology Protein Science Biochemistry

Proteomics –Genomics Some fundamental differences GenomeGenomics analysis proteomeProteome analysis DNA Nc-RNA mRNACoding DNAProteins Peptides Glyco, other modifications linearDynamic Up/down 3DDynamic Up/ down variants Completion Archived (EST, cDNA, GEO No notion of completion Poorly archived Encoded information Partially encoded

Proteomics – Genomics Even more different… Gene/ RNA dynamic Protein dynamic Stable molecules Handling cheap/ easy Minimal modification Works in isolation Fragile molecules Handling dependent Labile modification Protein-interaction Localization 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 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 I sequence, 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 Accuracy Efficient 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? P2P A patch of receptors P2P A patch of receptors Localization A pool of receptors Localization A pool of receptors Signaling Phospho. Endocytosis Signaling Phospho. Endocytosis PTM Ubiquitination of receptors PTM Ubiquitination of receptors Life time Proteosome action Life time Proteosome 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 next C lassifying Noisy Data The Ig case Yu et al P rotein Function Prediction- Kernels Borgwardt at al Substrate Prediction – Caspase Garay-Malpartida et al ****************************** Transmembrane domains for classification Sdaka & Linial Protein-protein Interaction and NMR Mettu et al