Michal Linial Institute of Life Sciences The Hebrew University Jerusalem, Israel Computer Science and Engineering University of Washington, Seattle ISMB 2005 Detroit, June 27 th 2005 Proteome 1
Proteome – by the dictionary • 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.
Proteomics – by the dictionary Proteomics (Practical) - the study of the proteome using technologies of large-scale protein separation and identification. Large scale separation : 2 DE Liquid Chromatography Identification : MALDI MS Tandem MS/MS FT-MS …. . Still to do: Imaging, Standardization, S/N…
Proteomics by Medline maturation of a field From 220 publications in the previous millennium (‘ 94 -’ 99) To 21, 350 (!!!) publications in this millennium (‘ 00 -’ 05) 1730
Proteomics –by Google the ultimate truth. . Proteomics Genomics 886, 000 hits (2004) 4, 700, 000 hits (2005) 2, 070, 000 hits (2004) 16, 000 hits (2005)
Proteomics – in view of other fields Genome Protein Science Genomics Structural proteome Biochemistry Cell Biology Database Molecular Application evolution Data Biotechnology Mining Nanotechnology Imaging Chemistry Proteome Proteomics
Proteomics –Genomics Some fundamental differences Genome Genomics analysis co de d linear Proteome analysis m. RNA DNA En Nc-RNA proteome Coding DNA Proteins Peptides Glyco, other modifications Pa rti in fo Dynamic rm Up/down at io Completion n Archived (EST, c. DNA, GEO 3 D al ly en No notion of completion Dynamic co Up/ down de variants d Poorly archived
Proteomics – Genomics Even more different… Gene/ RNA dynamic Stable molecules Fragile molecules Handling cheap/ easy PC Minimal. Rmodification – am Works in isolation Handle Protein dynamic Handling dependent No Labile P modification CR Protein-interaction eq Localization dependent u pl Tech HTP ifi Sequencing (established) ti iv le MS related (notayet) nt DNA array / genotyping/ expression / CGH/ Protein Chip (not yet) Antibodies array (not yet) ca on
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 Sequence space 2, 000 Structure space 20, 000 Function space 30, 000 (function by GO)
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 P 2 P 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 Signaling Phospho. Endocytosis GABA - the major inhibitory P 2 P NT in the brain A patch No signal at the genome/ transcriptome Localization levels of receptors GABA related to Anxiety, mood disorder, epilepsy, Parkinson, Sleep… A pool Controlling the of receptors level of GABA response How? PTM Ubiquitination of receptors Life time Proteosome action
Proteome –ISMB Summary …and another sign of maturation 2004: 31 submission 2005: 46 submission (only 16 full papers) (Structure, Pathways - not included) MS and 2 D related analysis Protein-interaction Protein Prediction Analysis Seq to function Annotation Specific Protein Families Localization related Others (modeling. . ) 10 9 8 7 5 3 4
What’s next Classifying Noisy Data The Ig case Yu et al Protein 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
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