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JELLY Report Summary

Project ID: 306435
Funded under: FP7-IDEAS-ERC
Country: Spain

Final Report Summary - JELLY (Biomolecular Hydrogels – from Supramolecular Organization and Dynamics to Biological Function)

Nature has evolved complex materials that are exquisitely designed to perform specific functions. Certain proteins and glycans self-organize in vivo into soft and dynamic, strongly hydrated gel-like matrices. An illustrative example of such biological hydrogels are the various extracellular matrices that surround the cells of our body. Even though biological hydrogels are ubiquitous in living organisms and fulfill fundamental biological tasks, we have today a very limited understanding of their internal organization, and how they function. The main reason is that this type of assemblies is difficult to study with conventional biochemical methods.

In order to study biological hydrogels directly on the supramolecular level, we have developed an unconventional approach that draws on knowledge from several scientific disciplines. Exploiting surface science tools, we tailor-make model systems by directed self-assembly of purified components on solid supports. With a toolbox of biophysical characterization techniques, these model systems are investigated quantitatively and in great detail. The experimental data, combined with soft matter physics theory and complementary molecular and cell-based assays, allow us to develop a better understanding of the relationship between the supramolecular organization and dynamics of biological hydrogels, their physico-chemical properties and their biological function. The project focused on two types of biomolecular hydrogels: the nuclear pore permeability barrier and extracellular matrices rich in the polysaccharide hyaluronan.

The transport of macromolecules between the nucleus and the cytosol is essential for gene transcription and translation and thus eukaryotic life and gated by the nuclear pore permeability barrier, a nanoscopic protein meshwork in the pores of the nuclear envelope. Our studies with in vitro reconstituted model systems have brought new understanding as to how selective gating works. We have established that basic principles of nuclear pore permselectivity, which have eluded biologists for many years, can be understood by adapting knowledge from the physics of polymers and soft matter. Our findings challenge a prominent hypothesis (the ‘reversible collapse’ model) and have led to the 'compacted meshwork' and later the ‘sticky spaghetti with meatballs’ model. These models unify the so-called 'entropic brush' and 'gel' models to explain how many weak attractive interactions within the protein meshwork in the nuclear pore control and optimize size selectivity. The insights gained also provide important guidelines for the design of biomimetic systems that can work as highly specific sieves or even performs active and directed transport for biotechnological applications.

Hyaluronan-rich matrices are important regulators of cellular processes in physiology and disease, including inflammation, fertilization and tumor metastasis. In this research area, our work has made three main contributions. Firstly, we demonstrated how hyaluronan targets a desired density of its main cell surface receptor CD44. The ability to selectively target a given receptor density is called ‘superselectivity’, and hyaluronan is the first molecule that has been demonstrated to have this capacity. Our insights may enable the rational design of a new generation of ‘superselective’ probes for application in a broad range of analytical, diagnostic, and therapeutic applications. Secondly, we revealed molecular mechanisms underlying remodeling and stabilization of hyaluronan-rich matrices around oocytes which are essential for fertility. This work demonstrated that three proteins are sufficient to cross-link and thus stabilize the matrices. It provided important new insight as to how the broad range of hyaluronan biology arises from the complexity and diversity of hyaluronan-protein interactions, and guidelines for the in vitro reconstitution of oocyte matrices which would be useful for fundamental studies and biomedical applications. Thirdly, we have elucidated how individual bonds between hyaluronan and its receptors respond to mechanical forces. This insight helps to understand how immune cells travel from the blood circulation into inflamed tissues and then further into the lymphatics as part of the body’s immune response, and may help develop new methods to avoid cancer cells hijacking these routes for cell migration.

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