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Molecular Adhesion and Interactions in the Nervous system

Periodic Reporting for period 4 - MAIN (Molecular Adhesion and Interactions in the Nervous system)

Reporting period: 2020-09-01 to 2021-06-30

Interactions and communication between cells in our body is important for the function and formation of tissues. Cells interact to provide mechanic support and shape organs, and cells exchange signals in order to function coherently. Disruption of these processes can lead to pathologies ranging from cancer to developmental disorders. The interaction and communication between cells is for a large part organized by proteins expressed on cell surfaces. On the cell surface these proteins can act as receptors or as ligands to receive or send signals from one cell to the other. In addition, these proteins can interact between cells and form adhesion complexes to shape our organs. It is not well understood how cell-surface expressed proteins organize themselves to control intercellular signaling and adhesion but previous results have shown that protein structures, interactions and conformational changes are the driving forces.

In this project we use two important protein signaling and adhesion systems, Notch and Contactin, to better understand the molecular mechanisms that underlie signaling and adhesion. The Notch and Contactin family of proteins play key roles in the development and function of several organs including our nervous system. Aberrant function of these proteins leads to the development of cancers and neurological disorders. Questions that we are addressing are: How do proteins interact in isolation and in a membrane setting? How does ligand binding induce receptor signaling? How are signaling and adhesion assemblies formed? These detailed mechanistic and structural insights will provide a molecular basis for understanding signaling and adhesion events. And ultimately these insights will help in the development of therapeutics that target diseases caused by malfunction of adhesion processes and intercellular signaling.
The receptors and ligands involved in intercellular adhesion and signaling are often large, consist of multiple domains (up to 40 for the Notch extracellular segment) and are post-translationally modified. We have established the production and purification of most proteins as planned. In particular the production and purification of the Notch1 and Jagged1 full ectodomains has been challenging but we were able to obtain mg quantities of high-quality samples for our subsequent work. The Notch1 receptor and its Jagged1 ligand play critical roles in the development and homeostasis of tissues and they can interact in cis (on the same cell) and in trans (between cells) for their function. We have shown that multiple sites in these multidomain proteins can interact intra- and inter-molecularly and that functionally important sites previously thought to be distal can in fact interact directly. This work has been presented at international and national conferences and has been published (Zeronian et al, 2021 PNAS doi.org/10.1073/pnas.2102502118).
In addition, for the contactin adhesion system we have produced and purified extracellular segments, determined interactions between proteins and established the oligomeric state for many of the samples. Structural studies have revealed detailed insights explaining how these proteins work as adhesion systems controlling cell-cell contacts. This work has been presented at international and national conferences and has been submitted for publication.
The structural, biophysical and biochemical insights that we have obtained are novel and reveal the mechanistic details of how interactions and structures work together to organize cell-cell signaling and communication.