Dr Ralf Richter

Profile

• Associate Professor at University of Leeds since 2016.
• Chair of Excellence, later Visiting Scientist, at University Grenoble Alpes (France; since 2012).
• Research Group Leader at CIC biomaGUNE (San Sebastian, Spain; 2007-18).
• Postdoctoral work at University of Heidelberg (2005-07).

Research interests

We aim to understand the mechanisms of assembly and function of soft biological interfaces, to advance knowledge and for applications in the life sciences

We are particularly interested in extracellular matrices that are rich in glycans; these microscopic hydrogel-like assemblies are important regulators of cell function and inter-cellular communication. Another main object of our research is the nuclear pore permeability barrier, a nanoscopic meshwork of intrinsically disordered proteins that makes macromolecular transport between the cytosol and nucleus of cells selective and is crucial for orderly gene expression. Resolving how these systems work provides new approaches to prevention, diagnosis and treat disease, and inspiration for the design of new functional materials.

To understand how biological functions emerge from the assembly and dynamic reorganization of biomolecules, we adopt a multidisciplinary approach that combines living cells and tissues with well-controlled models of tunable complexity. Exploiting surface science and engineering tools, we tailor-make model systems by the directed self-assembly of purified components on solid supports. For the quantitative analysis of these biomimetic systems, we develop a toolbox of physico-chemical in situ analysis techniques including quartz crystal microbalance (QCM-D), atomic force microscopy (AFM), spectroscopic ellipsometry (SE) and advanced optical microscopy methods. We use concepts from biological and soft matter physics to rationalize the properties of soft biological matter, and collaborate closely with biochemists and biologists to integrate our bottom-up biosynthetic approach with work at the levels of molecules, cells and living organisms.

The Lab in Leeds

For our research at the cross-roads of biology, physics, chemistry and engineering, we are affiliated with the School of Biomedical Sciences and the School of Physics and Astronomy. We are also part of the Astbury Centre for Structural and Molecular Biology.

Hyaluronan-rich extracellular matrices

Many cells surround themselves with a hydrogel-like matrix that is rich in the polysaccharide hyaluronan (HA). Such matrices are important in physiology and disease, and have unique properties. For example, we have found the HA matrix surrounding mammalian oocytes during ovulation and fertilization (also called cumulus cell-oocyte complex matrix) to be the softest elastic biological material reported to date (Chen et al. 2016).

Using in vitro reconstituted HA matrices, we define biochemical and physico-chemical mechanisms underlying the cross-linking (Baranova et al. 2011, Baranova et al. 2013, Baranova et al. 2014), remodelling (Attili et al. 2013) and solvation of HA-rich matrices, and how they interact with cells (Dubacheva et al. 2015). This provides important new insight as to how the complexity of glycan-protein interactions contributes to physiological processes such as inflammation and ovulation, cartilage function, immune cell recruitment and tumour metastasis.

Multifunctional signaling platforms to probe extracellular matrix assembly and cell fate

The controlled adhesion and oriented migration of cells are fundamental processes in physiology and disease. Chemokines (signaling proteins in the extracellular space) drive these processes, and glycosaminoglycans (GAGs; a family of linear polysaccharides) are responsible for organizing and presenting the chemokines thus playing key roles in regulating cellular behavior. Probing the molecular mechanisms that drive these phenomena in vivo is challenging. We design biomimetic surfaces to study GAG-protein interactions on the molecular and supramolecular levels, and to probe cellular responses to defined biochemical and biophysical cues to better understand GAG-mediated cell-cell and cell-matrix communication.

With our "molecular breadboard" technology (Migliorini et al. 2014, Thakar et al. 2014), we can assemble GAGs, chemokines and other extracellular matrix components such as cell adhesion ligands into multifunctional surfaces that are tailored to recapitulate selected aspects of the in vivo situation. These model surfaces are used as tunable artificial signaling platforms to study matrix assembly or to turn selected outside-in cellular signaling pathways on. With this platform, we have demonstrated that chemokines and growth factors differentially cross-link GAGs, and thus propose a novel regulatory function of these signaling proteins (Migliorini et al. 2015; Dyer et al. 2017). We have also shown that the binding of chemokines to GAGs plays critical roles in cell adhesion and migration (Thakar et al. 2017). For example, GAG-bound chemokines can promote cell adhesion even in the absence of any established cell adhesion ligand, and potentiate cell adhesion when such ligands are presented (Migliorini et al. 2014, Thakar et al. 2017). The artificial signaling platforms enable mechanistic studies of the cross-talk between different cell surface receptors and thus help providing a better understanding of how extracellular signals drive cell behavior. They may also prove useful as "niches" to control cellular fate, e.g. for stem cells.

Superselective targeting of cells and tissues

A basic requirement in biomedical research is the ability to specifically target cells and tissues. Targeting typically relies on the specific binding of a "ligand" on a tailor-made probe to a "receptor" on the desired cell/tissue. Conventional probes efficiently distinguish a biological entity displaying the receptor from others that do not, but selectivity is limited when the entities to be distinguished display a given receptor at different densities.

Using well-defined model systems based on host-guest chemistry, we could show that multivalent probes that bind several receptors simultaneously can sharply discriminate between different receptor densities (Dubacheva et al. 2014), and revealed how the extracellular matrix polysaccharide hyaluronan tunes such "superselective" binding to target specific cells, which is important in biological processes such as inflammation and tumour development (Dubacheva et al. 2015). This work helps to understand the regulation of multivalent interactions in biological systems and provides means for the rational design of a new generation of analytical, diagnostic and therapeutic probes with superselective targeting properties.

The Permeability Barrier of Nuclear Pore Complexes

Macromolecular transport between the cytosol and the nucleus of living cells is essential for the ordered course of gene expression. This transport occurs through nuclear pore complexes (NPCs) that perforate the nuclear envelope and is selective: objects beyond a certain size (30 kDa) need to attach to soluble nuclear transport receptors (NTRs) in order to be channelled efficiently through the pore. A supramolecular assembly of specialized and natively unfolded protein domains (FG nups) within the NPC acts as permeability barrier, but how this self-organized polymer meshwork generates transport selectivity is only poorly understood.

We aim to understand the relation between the organizational and dynamic features of FG-nup assemblies, their physico-chemical properties, and the resulting biological functions. By combining experiments on tailor-made biomimetic systems (Eisele et al. 2010; Eisele et al. 2012) with polymer physics theory, we quantitatively study these relationships on the supramolecular level, a level that for this type of assemblies is hardly accessible with conventional biological and biophysical approaches. We find that simple polymer physics models that treat FG nups as flexible and sticky, regular polymers and NTRs as featureless spheres describes the self-organization of FG nups (Eisele et al. 2013) and their interactions with NTRs (Zahn et al. 2016) remarkably well, despite the intrinsic complexity of these biomolecules. This work is increasing our mechanistic understanding of nuclear transport and also provides guidelines for the rational design of novel artificial separation devices for biotechnological applications.

• Action in solution: Embedding new technology and new capability in Biomolecular Interactions in the University of Leeds
• Defining the role of cell glycocacalyces in cell trafficking at endothelial walls
• Molecular mechanisms underpinning nuclear pore permselectivity - A polymer physics approach
• Revealing complexity of polysaccharide-protein interactions
• Superselective targeting of cells through multivalent lectin-glycan interactions
• Understanding hyaluronan crosslinking mechanisms in ovulation and inflammation: CryoEM structural and interaction analysis of HC-HA/PTX3 complexes

Qualifications

• PhD, Physical Chemistry, University Bordeaux I
• MSc, Physics, Chalmers/Göteborg University, Sweden

Student education

I am teaching to undergraduate and postgraduate students in Biomedical Sciences and in Physics.

Studentship information

Student projects:

• We have various projects available for undergrad and postgraduate students. We also accept applications by self-funded students to work in our multidisciplinary team. Please get in touch if you are interested.

See also:

• Faculty Graduate School

Current postgraduate researchers

• Ashleigh Goodenough

Projects

<li><a href="//phd.leeds.ac.uk/project/1114-mapping-the-nanoscale-organisation-of-cellular-proteins-across-complex-topographies">Mapping the nanoscale organisation of cellular proteins across complex topographies</a></li>