1. Nature’s logistical solution
Zoltan Maliga
MPI-CBG
CCSS International Worksop
June 8-12, 2009

2. 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

3. 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

4. Can we look for control points in a process?
DNA
Tubulin

5. 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?

6. Capitalizing on checkpoints to treat cancer
DNA
Tubulin

7. Scaling in biology
Tubulin polymerization
Nutrient uptake, cell division
Cell movement, shape, organization
Forming connections between cells
Brain function, immunology, physiology
Reductionism
Integrationism

8. Exploring an infinite-parameter space
Predicted activity
conventional
genomics
genes
Function
processes
compartments
Interactions

9. How is a cell physically organized?
parts list
neuron
brain

10. 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

11. 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

12. Known motors are properly targeted in cell division
GENE OF STUDY
GFP

13. Each motor has a unique localization pattern

14. A physical interaction map of the cell
Virus infection
Nutrient uptake
Cell motion
Cell division
Kidney disease
Mitochondrial disease
Mental retardation
DNA alignment

15. From data to function : Understanding mitochondria

16. Motor labels moving strings in cells
MYO19
DNA

17. Motor is not on filament 1
MYO19
Calnexin
F-Actin

18. Motor is on filament 2
Galectin
MYO19
a-tubulin

19. Motor surrounds mitochondria (generates energy)

20. Maintaining mitochondria for energy production
branching
fusion
fission
Gene
Filament 1
Fis1

21. 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

22. 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)

23. TITLE