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Mechanisms of protein SUMOylation and its functional consequences

Description du projet

Profilage de la SUMOylation: ligases E3 la soutenant et effets en aval

Les petits modificateurs de type ubiquitine (SUMO), découverts il y a environ 25 ans, sont des membres de la superfamille des polypeptides de type ubiquitine. Ces polypeptides se fixent de manière covalente aux protéines cibles intracellulaires, modifiant leur fonction, leur emplacement ou leur stabilité. La SUMOylation joue un rôle essentiel dans de nombreuses fonctions biologiques, notamment la croissance et la migration cellulaires, la tumorigenèse, la stabilité génomique et l’infection. La SUMOylation repose généralement sur des enzymes appelées ligases E3. Peu d’enzymes SUMO E3 ont été identifiées et caractérisées. Le projet SUMOwriteNread, financé par le CER, comblera cette lacune en identifiant la structure et le mécanisme d’action de certaines ligases SUMO E3, en développant des approches pour identifier et caractériser de nouvelles SUMO E3 et, enfin, en étudiant l’impact fonctionnel de la SUMOylation en termes de déclenchement de nouvelles protéines.

Objectif

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.

Institution d’accueil

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Contribution nette de l'UE
€ 1 493 515,00
Adresse
RUE MICHEL ANGE 3
75794 Paris
France

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Région
Ile-de-France Ile-de-France Paris
Type d’activité
Research Organisations
Liens
Coût total
€ 1 493 515,00

Bénéficiaires (1)