Project description
Taking a closer look at how cells 'talk' to each other
Cell-adhesion molecules (CAMs) play an important role in structuring the synaptic architecture through multifaceted interactions with a variety of synaptic partners and orchestrating neuronal communication. The EU-funded CellCellEM project will shed light on the mechanism governing CAMs' synaptic activities. Specifically, the project will combine single particle cryo-electron microscopy (cryo-EM), tomography and biochemical methodologies to dissect the molecular mechanisms of Latrophilins (LPHNs) – CAMs that mediate cell-cell communication at the synapse. The studies will aim at providing the structural basis for CAMs' function and will fully characterise the set of LPHN interactions with proteins at the central nervous system (CNS). The findings of the project will further enrich our knowledge of cell-cell communication in the CNS.
Objective
Synapses are intercellular junctions specialized for coordinated cell-cell communication throughout the nervous system. They are organized by cell-adhesion molecules (CAMs) that bi-directionally orchestrate neuronal communication. Latrophilins (LPHNs) are a unique sub-family of CAMs that play critical roles in structuring the synaptic architecture through multifaceted interactions with a large variety of synaptic partners. Mutations in LPHN have been associated with neurodevelopmental and neuropsychiatric disorders. Despite their gravity, the mechanism governing LPHN synaptic activities remain elusive.
To further our understanding of LPHN-mediated cell-cell communication, we suggest to characterize these receptors’ interactions with their intracellular and extracellular partners. For this purpose, we propose to adopt a hybrid approach driven primarily by cryo-EM, a state-of-the-art technique capable of dissecting the molecular mechanisms of super-molecular assemblies at extremely high spatial resolutions, which is our group’s main field of expertise. The cryo-EM studies will be complemented by cryo electron tomography (cryo-ET), fluorescence microscopy and biochemical approaches. Our specific aims are:
Aim 1: Dissect the molecular mechanisms of LPHN activation by combining cryo-EM with biochemical methodologies.
Aim 2: Characterize the LPHN interactome through cryo-EM and fluorescence microscopy.
Aim 3: Resolve the architecture of the LPHN interactome at a close-to-native environment through cryo-ET.
Our experimental strategy will generate a quantitative, near-atomic resolution view of LPHNs and the mechanism by which they interact with their synaptic partners and instigate trans-synaptic signal transduction. These data will be vital for understanding LPHN-mediated cell-cell communication as well as the mechanisms governing trans-synaptic interactions and could potentially highlight novel approaches to treat neurodevelopmental and neuropsychiatric disorders.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
7610001 Rehovot
Israel