Project description
Unveiling biomolecular condensates’ interaction with organelles
Cells contain dynamic structures known as biomolecular condensates that form through liquid-liquid phase separation of molecules. These condensates emerge from the assembly of various biomolecules, including proteins, nucleic acids, and sometimes lipids, and unlike traditional membrane-bound organelles, they lack a surrounding membrane. Funded by the European Research Council, the MEMLESSINTERFACE project aims to investigate the interaction between biomolecular condensates and membrane-bound organelles in neurons. The work will focus on biomolecular condensates formed at synapses, their regulation and interaction with mitochondria and the endoplasmic reticulum to mediate neuronal function.
Objective
Liquid-liquid phase separation is a major mechanism for organizing macromolecules, particularly proteins with intrinsically disordered regions, in compartments not limited by a membrane. Many such compartments (also known as biomolecular condensates) have been described, and it is currently agreed that they take over several cellular functions. To do so, they need to interact with other compartments, just as the membrane-bound organelles interact with each other through well-defined contact sites. However, at present no concept exists explaining how membrane-less and membrane-bound organelles interact.
I propose here to address this question by determining the molecular mechanisms and functional impact of the interactions between liquid phases and membranes. I hypothesize that a novel type of contact sites between membrane-less organelles and membranes, which I termed dipping contacts, is critical for coupling of diffusion and material properties of condensates to biochemical processes occurring in the membrane-bound compartments.
To test this, I will capitalize on a prominent biomolecular condensate that I characterized a few years ago, and which has already been used widely in the literature: the synaptic vesicle (SV) condensate, which clusters SVs together with proteins such as synapsins and synucleins. For this, I have already developed advanced reconstitution tools, single-molecule tracking and genetic code expansion in living neurons, which will enable me to determine: i) how the material properties of SV condensates are regulated, ii) how they recruit specific organelles, while rejecting others, iii) the proteins that mediate signaling and interactions of SV condensates with mitochondria and the ER.
Overall, this project will lead to an understanding of the interface between condensates and classical organelles, which is extremely relevant in the context of aggregation-related diseases where faulty inclusions of membranes and proteins play a leading role.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
53127 Bonn
Germany