Project description
Protein assembly in organelle organisation: is it time to revisit the history of biology?
We know that intracellular organisation into organelles relies on the formation of lipid bilayers and allows cells to compartmentalise different processes. However, the existence of non-membrane bound compartments, such as nucleoli, raises the question of how cells keep such regions distinct and prevent their context from mixing with the surroundings. The EU-funded LiquOrg project will challenge the concept that membrane-less organelles are formed by liquid-liquid phase separation and proposes a liquid crystal hypothesis where surface proteins organise into multiple layers which surround and enclose their membranes. Researchers will use the Golgi apparatus and the golgin proteins as proof of concept.
Objective
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).
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Funding Scheme
ERC-SyG - Synergy grantHost institution
75794 Paris
France