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Nature’s logistical solution
Zoltan Maliga MPI-CBG CCSS International Worksop June 8-12, 2009
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Biology : information, template, robust, adaptable
genetic blueprint diversity 6 x 109 bases in the genome 20,000 proteins 10,000 found in all cells Robust developmental program Trillions of cells Phenotypic archetypes Similar cognitive abilities ~10 Ma evolution common cell machinery cell-type specific genes
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Medicine : Fixing a molecular network
No effect Therapeutic Toxicity Death Dosage-regime In patients Stroke COX-1 COX-2 Stomach ulcers Pain killer Blood thinner
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Can we look for control points in a process?
DNA Tubulin
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Quality control subroutines ensure correct cell division
Conserved ATPase motor domain - couples filament binding to ATP hydrolysis Each motor is directional, as dimeric or array of motor proteins (processivity) Regulation between open and closed conformation (motor activity regulated by cargo binding or ‘cell state’ Some motors are expressed ubiquitously - with MANY roles in the same cell Other proteins highly tissue-specific (myosins, for example) Molecules hard-wired to interact Positive feed-back (amplification) Inducible negative feed-back Irreversible steps DNA attached? DNA separated? Cell divided?
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Capitalizing on checkpoints to treat cancer
DNA Tubulin
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Scaling in biology Tubulin polymerization Nutrient uptake, cell division Cell movement, shape, organization Forming connections between cells Brain function, immunology, physiology Reductionism Integrationism
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Exploring an infinite-parameter space
Predicted activity conventional genomics genes Function processes compartments Interactions
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How is a cell physically organized?
parts list neuron brain
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Agents of cell organization : Motor proteins in cells
DNA Tubulin Actin ACTIN TUBULIN What do they do? Where are they? What do they bind? 40 motors walk on actin 39 motors walk on tubuliln
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Experimental system : adding genes to cells
Gene (DNA) your favorite gene GFP Interaction Into cells Localization Partner complex INTEGRATE WITH CURATED DATA SETS Gene GFP
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Known motors are properly targeted in cell division
GENE OF STUDY GFP
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Each motor has a unique localization pattern
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A physical interaction map of the cell
Virus infection Nutrient uptake Cell motion Cell division Kidney disease Mitochondrial disease Mental retardation DNA alignment
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From data to function : Understanding mitochondria
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Motor labels moving strings in cells
MYO19 DNA
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Motor is not on filament 1
MYO19 Calnexin F-Actin
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Motor is on filament 2 Galectin MYO19 a-tubulin
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Motor surrounds mitochondria (generates energy)
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Maintaining mitochondria for energy production
branching fusion fission Gene Filament 1 Fis1
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SUMMARY Systematic analysis of all motor proteins Different motor proteins define unique compartments New discoveries on the control of cell division Novel disease-relevant interaction networks
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ACKNOWLEDGEMENTS Mental Retardation Hilger Ropers (MPI-MG, Berlin)
Cell Division Helder Maiato Stefano Maffini (U. Porto) Cell Motility Anna Akhmanova (U. Erasmus) Virology Beate Sodeik (U. Hannover) Drug Mechanism Nathanael Gray (Harvard Medical School) Merck, GmbH (Darmstadt)
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