Descrizione del progetto
Tracciare un profilo della sumoilazione: il contributo della ligasi E3 e gli effetti a valle
I piccoli modificatori simili all’ubiquitina (SUMO, Small Ubiquitin-like MOdifiers), scoperti circa 25 anni fa, appartengono alla superfamiglia dei polipeptidi simili all’ubiquitina. Questi polipeptidi formano legami covalenti con le proteine intracellulari bersaglio, modificandone la funzione, la posizione o la stabilità. La cosiddetta sumoilazione svolge un ruolo essenziale in numerose funzioni biologiche, tra cui la crescita e la migrazione cellulare, la tumorigenesi, la stabilità genomica e l’infezione. La sumoilazione dipende generalmente da enzimi chiamati ligasi E3, pochi dei quali sono stati identificati e caratterizzati. Il progetto SUMOwriteNread, finanziato dal CER, colmerà questa lacuna, identificando la struttura e il meccanismo di azione di alcune ligasi E3 SUMO, sviluppando approcci per identificarne e caratterizzarne di nuove e indagando in definitiva sull’impatto funzionale della sumoilazione in termini di attivazione di nuove proteine.
Obiettivo
Protein post-translational modification with small ubiquitin-like modifiers (SUMO1, -2, and -3), also known as SUMOylation, targets a third of human proteins, is essential for organisms from yeast to humans, and has strong links to cancer and neurodegeneration. Like ubiquitylation, to which it is related, SUMOylation typically depends on the action of enzymes called E3 ligases, which help determine substrate specificity and the exact signal that is produced. However, while for ubiquitylation several hundred E3s are known, no more than two dozen SUMO-specific E3s have been described and only four characterised structurally in a way that reveals their mechanism. Intriguingly, the SUMO E3 ligase activity keeps being detected in proteins that are unrelated to each other and sometimes can be mapped to apparent disordered regions. In the first part of this project, I will explore the poorly charted territory of SUMO writing by elucidating the structure and mechanism of some known SUMO E3 ligases for which the mechanism is unclear. This analysis will serve as a stepping stone to proposing computational, chemical biology, and structural biology approaches to identifying and characterising new SUMO E3s. In the second part, I will investigate downstream consequences of SUMOylation. Following attachment to a protein substrate, SUMOylation is thought to function as a “molecular glue” by promoting formation of protein complexes with specific SUMO “readers”, but detailed structural and biochemical information is lacking for any of such putative assemblies. To address this topic, I will develop strategies to identify and characterise SUMO-dependent complexes. The new tools, approaches, and knowledge about SUMO writing and reading will be broadly applicable to pathways regulated by SUMOylation, allowing their understanding in molecular and mechanistic terms. The study will also explore general concepts in protein evolution and evolutionary emergence of signalling systems.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
75794 Paris
Francia