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Mechanisms of protein SUMOylation and its functional consequences

Project description

Profiling SUMOylation: the E3 ligases subserving it and downstream effects

Small ubiquitin-like modifiers (SUMOs), discovered about 25 years ago, are members of the superfamily of ubiquitin-like polypeptides. These polypeptides become covalently attached to intracellular target proteins, modifying their function, location or stability. So-called SUMOylation plays an essential role in many biological functions including cell growth and migration, tumourigenesis, genomic stability, and infection. SUMOylation typically depends on enzymes called E3 ligases. Few SUMO E3 enzymes have been identified and characterised. The ERC-funded SUMOwriteNread project will fill this gap, identifying the structure and mechanism of action of some SUMO E3 ligases, developing approaches to identify and characterise new SUMO E3s, and finally to investigate the functional impact of SUMOylation in terms of triggering new proteins.

Objective

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.

Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 1 493 515,00
Address
RUE MICHEL ANGE 3
75794 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 1 493 515,00

Beneficiaries (1)