Descripción del proyecto
El ensamblaje proteico en la organización de los orgánulos: ¿ha llegado el momento de revisar la historia de la biología?
Sabemos que la organización intracelular en los orgánulos se basa en la formación de bicapas lipídicas y permite a las células compartimentar diferentes procesos. Sin embargo, la existencia de compartimentos no ligados a una membrana, como los nucleolos, lleva a plantearse cómo las células consiguen mantener separadas estas zonas y evitar que su contenido se mezcle con el entorno. El proyecto LiquOrg, financiado con fondos europeos, cuestionará el concepto según el cual los orgánulos sin membrana se forman por separación de fases líquido-líquido y propondrá la hipótesis del cristal líquido, en que las proteínas de superficie se organizan en varias capas que envuelven y encierran sus membranas. Los investigadores emplearán el aparato de Golgi y sus proteínas como prueba de concepto.
Objetivo
We are in the midst of a revolution in our understanding of the internal organization of cells. In the 1950s we learned that lipid bilayer-based membranes serve as containers (organelles) within the cytoplasm. Now we are learning that liquid-like “membrane-less” organelles i.e. without any container, self-assemble based on “liquid-liquid” phase separations. We propose the seemingly radical idea that membrane-bounded organelles– like their membrane-less counterparts- are stabilized or even templated by analogous phase separations of their surface proteins into largely planar liquids akin to liquid crystals. Our unique Synergy team is organized specifically to test this “liquid crystal hypothesis” on the cell’s secretory compartments - ER exit sites (ERES) and the Golgi stack - by employing our complementary skills in physics, physical chemistry, biochemistry and cell biology. We hypothesize based on pilot experiments evidence that the ERES and Golgi self-organize as a multi-layered series of adherent liquid crystal-like phases of “golgin” and similar proteins which surround and enclose their membranes. Their differential adhesion and repulsion would specify the topology and dynamics of the membrane compartments. If this is true, it will literally rewrite the history of cell biology.
We will test the ‘liquid crystal’ hypothesis directly, systematically, and quantitatively on an unprecedented scale to either modify/disprove it or place it on a firm rigorous footing. Experiments (Aim 1) with 13 pure golgins in cis and trans pairwise combinations will establish their foundational physical chemistry. Surgically engineered changes in golgins/ERES proteins will alter the rank order (hierarchy) of their affinities for each other and link phase separation physics to cell biology (Aim 2) and be used to establish the structural basis of phase separations and their specificity, and the potential for self-assembly of wholly synthetic biological organelles (Aim 3).
Ámbito científico
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Programa(s)
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Régimen de financiación
ERC-SyG - Synergy grantInstitución de acogida
75794 Paris
Francia