Descripción del proyecto
Análisis de sumoilación: las ligasas E3 implicadas y los efectos posteriores
Los pequeños modificadores relacionados con la ubicuitina (SUMO, por sus siglas en inglés), descubiertos hace unos veinticinco años, pertenecen a la superfamilia de polipéptidos relacionados con la ubicuitina. Estos polipéptidos se unen de forma covalente a proteínas intracelulares diana y modifican su función, ubicación o estabilidad. La sumoilación desempeña un papel fundamental en muchas funciones biológicas como, por ejemplo, el crecimiento y la migración celular, la oncogénesis, la estabilidad genómica y las infecciones. Este proceso suele depender de unas enzimas denominadas «ligasas E3». Hasta la fecha, se han identificado y caracterizado pocas enzimas SUMO E3. El equipo del proyecto SUMOwriteNread, financiado por el Consejo Europeo de Investigación, colmará este vacío al identificar la estructura y el mecanismo de acción de algunas ligasas SUMO E3, desarrollar métodos para identificar y caracterizar nuevas SUMO E3 y, por último, investigar el efecto funcional de la sumoilación en términos de activación de nuevas proteínas.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
75794 Paris
Francia