UBIQUITIN BALANCE
The balance of ubiquitin conjugation and deconjugation
| Coordinatore | STICHTING HET NEDERLANDS KANKER INSTITUUT
Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie. |
| Nazionalità Coordinatore | Netherlands [NL] |
| Totale costo | 2˙299˙720 € |
| EC contributo | 2˙299˙720 € |
| Programma | FP7-IDEAS-ERC
Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | ERC-2009-AdG |
| Funding Scheme | ERC-AG |
| Anno di inizio | 2010 |
| Periodo (anno-mese-giorno) | 2010-02-01 - 2015-01-31 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
STICHTING HET NEDERLANDS KANKER INSTITUUT
Organization address
address: PLESMANLAAN 121 contact info |
NL (AMSTERDAM) | hostInstitution | 2˙299˙720.00 |
| 2 |
STICHTING HET NEDERLANDS KANKER INSTITUUT
Organization address
address: PLESMANLAAN 121 contact info |
NL (AMSTERDAM) | hostInstitution | 2˙299˙720.00 |
Mappa
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Obiettivo del progetto (Objective)
Ubiquitin conjugation is one of the most important signaling systems in the eukaryotic cell. Different types of mono- and polyubiquitin chains determine the fate of target proteins by redirecting them for degradation, relocalization or interaction with new partners. The type of ubiquitin modification on any target is determined by the interplay between the conjugating E2/E3 complexes on the one hand and deubiquitinating enzymes on the other. In practice, it is the balance between conjugating and deconjugating systems that determines the result of the various ubiquitination signals. For three different regulatory systems that are critical for correct genome maintenance, we are now in a position to study not just the individual process of conjugation or deconjugation in isolation, but rather, reconstitute the entire reaction on a defined physiological target. These three target systems, histone H2A, PCNA and P53, can be mono-ubiquitinated by a defined E3-ligase, poly-ubiquitinated by a second ligase and deconjugated by defined deubiquitinating enzymes in a reaction that is affected by known allosteric modulators. Our unique collection of tools to study these systems in vitro allows reconstitution of the full reaction, to trap intermediates, and to study their interaction from atomic detail to kinetic reactivity. Using X-ray crystallography of critical intermediates and kinetic analysis of individual reactions by FRET and surface plasmon resonance, we can address how the mono-, poly and deubiquitinating reactions affect each other. By answering mechanistic questions on the relative effect of the forward and backward reaction components and their modulators we will provide a solid basis for drug design studies that target these pathways against cancer development.