Role of the mechanical micro-environment in early stages of cadherins junction formation

• Applicant: Professorin Dr. Ana-Suncana Smith
• Subject Area: Biophysics
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406909831

Cadherins, which are a large family of receptors residing on the plasma membrane, are instrumental in the adhesion of cells in a variety of tissues. Typically, they aggregate into micron size adherens junctions, in the environment comprising the glycocalyx, the plasma membrane and the cytoskeleton. As they mature, the junctions attach to actin through a unique macromolecular complex. Traditionally, this attachment was thought to be associated with the late stage of junction formation, but more recent experiments on cell/model-membrane hybrids indicate that even the formation of initial E-cadherin contacts may necessitate active interaction of the cadherin intracellular domain with the cytoskeleton. It was speculated that unlike for most ligand/receptor pairs, this makes cadherin adhesion uniquely dependent on prior binding to the cytoskeleton. However, E-cadherin contacts can also form in purely model membranes in the form of cytoskeleton-free functionalized vesicle (GUV) supported & lipid bilayer (SLB) system, where we recently showed that the self-organization of cadherins into micro-domains is regulated by membrane fluctuations. Upon the establishment of nano-clusters, different morphology and dynamics of growth of cadherin aggregates are regulated by fine changes in fluctuations, qualitatively not different to what was previously found for other ligand-receptor pairs. The particularly high sensitivity to fluctuations was found to originate in the intrinsically low affinity of cadherins for trans-dimerisation. Membrane fluctuations were shown to stabilize lateral cis-domains by purely generic interactions. We therefore hypothesize that the role of cytoskeleton in cadherin mediated cell adhesion is to generate active fluctuations that give rise to long range cis-interactions and tune the effective cadherin reaction rates and affinities. Past studies by us and others have now established that beside the biochemical regulation emphasized in the past for cells, phenomena associated with the fluctuating membrane microenvironment, as well as glycocalyx and ligand mobility provides mechanical control parameters for the development of adhesion junctions. The relevance of this mechanical milieu remains disputed in the context of cells. The aim of this proposal is to resolve this debate by elucidating the relative roles of specific and generic interactions, and provide a deeper understanding of the dynamics of the aggregation and binding of cadherins in the early stages of junction development. Building on our excellent track record in adhesion, we will address this goal by improving on the state of the art synthetic models based on vesicles and cells, and studying them with top of the range experimental techniques. Sophisticated imaging, data analysis, supported by comprehensive theoretical modeling will provide a sound conceptual framework to understand the early stages of the cadherin based junction formation and its mechanical regulation.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professorin Kheya Sengupta, Ph.D.