Skip to main content
European Commission logo print header

Molecular structure and cell cycle regulated assembly of the kinetochore

Descripción del proyecto

Arquitectura y función de las proteínas de la división celular

Durante la división celular eucariota, la replicación y segregación fiel del material genético en las células hijas es un paso crucial. Los cromosomas se alinean y se unen al huso mitótico formado por microtúbulos a través de sus centrómeros y un grupo de proteínas conocidas como cinetocoros. El proyecto MolStruKT, financiado por el Consejo Europeo de Investigación, tiene como objetivo investigar la arquitectura nativa de los complejos cinetocóricos en células humanas y en la levadura. Los investigadores estudiarán las interacciones entre proteínas y los cambios de fosforilación a fin de dilucidar la estructura y el control temporal del ensamblaje del cinetocoro. El conocimiento de la estructura y función del cinetocoro permitirá comprender mejor la segregación cromosómica y los trastornos relacionados, como la aneuploidía y la tumorigénesis.

Objetivo

Accurate chromosome segregation in eukaryotes requires the assembly of the macromolecular kinetochore complex at centromeres to attach chromosomes to the mitotic spindle. The kinetochore proteins are organized in stable subcomplexes that bind to dynamic microtubules and ensure fidelity of sister chromatid separation through feedback control. Characterizing the kinetochore structure will significantly advance our understanding of chromosome segregation and how defects in this process can lead to aneuploidy, which is associated with tumorigenesis. X-ray crystallography has provided detailed insights into the function of subcomplexes, however, a molecular analysis of the native kinetochore subunit architecture is still missing. I have recently combined chemical cross-linking with mass spectrometry (CXMS) which allows for the first time the topological analysis of native macromolecular protein structures by a comprehensive set of distance restraints. Applying this approach to kinetochores assembled on budding yeast minichromosomes I aim to elucidate the architecture of the native centromere-assembled kinetochore complex and analyze how tension sensing by the chromosomal passenger complex is integrated into the structure. Secondly, the systematic analyses of changes in phosphorylation levels and in protein stoichiometries of soluble and nucleosome-associated human kinetochore complexes will reveal how the tight temporal control of assembling a functional kinetochore in mitosis is achieved. Thirdly, I will investigate the architecture of the centromere-associated network of kinetochore proteins by CXMS to unveil its role in directing CENP-A replenishment at mitotic exit in order to maintain centromere identity through generations. The analysis of the native kinetochore structure in different functional states will provide fundamental mechanistic insights and help us to understand how this architecture confers fidelity to centromere propagation and chromosome segregation.

Régimen de financiación

ERC-STG - Starting Grant

Coordinador

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Aportación neta de la UEn
€ 1 499 932,00
Dirección
Geschwister scholl platz 1
80539 Muenchen
Alemania

Ver en el mapa

Región
Bayern Oberbayern München, Kreisfreie Stadt
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 1 499 932,00

Beneficiarios (1)