Projektbeschreibung
SUMOylierung im Profil: versorgende E3-Ligasen und nachgeschaltete Effekte
Die vor etwa 25 Jahren entdeckten kleinen ubiquitinähnlichen Modifikatoren (Small Ubiquitin-Related Modifier, kurz SUMO) gehören zur Superfamilie der ubiquitinähnlichen Polypeptide. Diese Polypeptide werden kovalent an intrazelluläre Zielproteine gebunden und verändern deren Funktion, Position oder Stabilität. Die sogenannte SUMOylierung übernimmt bei vielen biologischen Funktionen wie Zellwachstum und -migration, Tumorentstehung, Genomstabilität und Infektionen eine Hauptaufgabe. Die SUMOylierung hängt typischerweise von Enzymen ab, die als E3-Ligasen bezeichnet werden. Bisher konnten nur wenige SUMO-E3-Enzyme erkannt und charakterisiert werden. Das ERC-finanzierte Projekt SUMOwriteNread wird diese Lücke schließen, indem es die Struktur und den Wirkmechanismus einiger SUMO-E3-Ligasen ermittelt, Ansätze zur Identifizierung und Charakterisierung neuer SUMO-E3s entwickelt und letztlich die funktionellen Auswirkungen der SUMOylierung im Hinblick auf die Auslösung neuer Proteine untersucht.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
ERC - Support for frontier research (ERC)Gastgebende Einrichtung
75794 Paris
Frankreich