Background: MSc in Physics (Chalmers/Göteborg University, Sweden). PhD in Physical Chemistry (University Bordeaux I, France; 2004). Postdoctoral work at University of Heidelberg (2005-07). Research Group Leader at CIC biomaGUNE (San Sebastian, Spain; since 2007). Chair of Excellence, later Visiting Scientist, at University Grenoble Alpes (France; since 2012). Associate Professor at University of Leeds since 2016.
Contact: Garstang 5.55r, +44(0) 113 34 31969,
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.
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). We have also shown that matrix-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). 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.
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.
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 channeled 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.
BIOL5294M - MSc Bioscience Research Project Proposal
BIOL5392M - Bioscience MSc Research Project
Group Leader Dr Ralf Richter (Associate Professor)
We aim to understand the mechanisms of assembly and function of soft biological interfaces, to advance knowledge and for applications in the life sciences.
Mr Thomas Lewis Adams (Research Technician)
Dr Fouzia Bano (Research Fellow)
Probing the dynamics of glycosaminoglycan-proteins interactions under force
Dr Rickard Frost (Research Fellow)
Miss Marta Sobrinos Sanguino (Research Technician)
Thakar D, Dalonneau F, Migliorini E, Lortat-Jacob H, Boturyn D, Albiges-Rizo C, Coche-Guerente L, Picart C, Richter RP Binding of the chemokine CXCL12α to its natural extracellular matrix ligand heparan sulfate enables myoblast adhesion and facilitates cell motility Biomaterials 123 24-38, 2017
Dubacheva GV, Araya-Callis C, Geert Volbeda A, Fairhead M, Codée J, Howarth M, Richter RP Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin. Journal of the American Chemical Society 139 4157-4167, 2017
Dyer DP, Migliorini E, Salanga CL, Thakar D, Handel TM, Richter RP Differential structural remodelling of heparan sulfate by chemokines: The role of chemokine oligomerization Open Biology 7 -, 2017
Bano F, Banerji S, Howarth M, Jackson DG, Richter RP A single molecule assay to probe monovalent and multivalent bonds between hyaluronan and its key leukocyte receptor CD44 under force Scientific Reports 6 -, 2016
Chen X, Bonfiglio R, Banerji S, Jackson DG, Salustri A, Richter RP Micromechanical Analysis of the Hyaluronan-Rich Matrix Surrounding the Oocyte Reveals a Uniquely Soft and Elastic Composition Biophysical Journal 110 2779-2789, 2016
Zahn R, Osmanović D, Ehret S, Callis CA, Frey S, Stewart M, You C, Görlich D, Hoogenboom BW, Richter RP A physical model describing the interaction of nuclear transport receptors with FG nucleoporin domain assemblies eLife 5 -, 2016
Briggs DC, Birchenough HL, Ali T, Rugg MS, Waltho JP, Ievoli E, Jowitt TA, Enghild JJ, Richter RP, Salustri A, Milner CM, Day AJ Metal Ion-dependent heavy chain transfer activity of TSG-6 mediates assembly of the cumulus-oocyte matrix Journal of Biological Chemistry 290 28708-28723, 2015
Migliorini E, Thakar D, Kühnle J, Sadir R, Dyer DP, Li Y, Sun C, Volkman BF, Handel TM, Coche-Guerente L, Fernig DG, Lortat-Jacob H, Richter RP Cytokines and growth factors cross-link heparan sulfate Open Biology 5 -, 2015
Osypova A, Thakar D, Dejeu J, Bonnet H, Van Der Heyden A, Dubacheva GV, Richter RP, Defrancq E, Spinelli N, Coche-Guérente L, Labbé P Sensor Based on Aptamer Folding to Detect Low-Molecular Weight Analytes Analytical Chemistry 87 7566-7574, 2015
Borisova OV, Billon L, Richter RP, Reimhult E, Borisov OV PH- and Electro-Responsive Properties of Poly(acrylic acid) and Poly(acrylic acid)-block-poly(acrylic acid-grad-styrene) Brushes Studied by Quartz Crystal Microbalance with Dissipation Monitoring Langmuir 31 7684-7694, 2015
Dubacheva GV, Curk T, Auzély-Velty R, Frenkel D, Richter RP Designing multivalent probes for tunable superselective targeting Proceedings of the National Academy of Sciences of the United States of America 112 5579-5584, 2015
De Gernier R, Curk T, Dubacheva GV, Richter RP, Mognetti BM A new configurational bias scheme for sampling supramolecular structures Journal of Chemical Physics 141 -, 2014
Thakar D, Migliorini E, Coche-Guerente L, Sadir R, Lortat-Jacob H, Boturyn D, Renaudet O, Labbe P, Richter RP A quartz crystal microbalance method to study the terminal functionalization of glycosaminoglycans Chemical Communications 50 15148-15151, 2014
Baranova NS, Inforzato A, Briggs DC, Tilakaratna V, Enghild JJ, Thakar D, Milner CM, Day AJ, Richter RP Incorporation of pentraxin 3 into hyaluronan matrices is tightly regulated and promotes matrix cross-linking Journal of Biological Chemistry 289 30481-30498, 2014
Van Der Meulen SAJ, Dubacheva GV, Dogterom M, Richter RP, Leunissen ME Quartz crystal microbalance with dissipation monitoring and spectroscopic ellipsometry measurements of the phospholipid bilayer anchoring stability and kinetics of hydrophobically modified DNA oligonucleotides Langmuir 30 6525-6533, 2014
Dubacheva GV, Curk T, Mognetti BM, Auzély-Velty R, Frenkel D, Richter RP Superselective targeting using multivalent polymers Journal of the American Chemical Society 136 1722-1725, 2014
Migliorini E, Thakar D, Sadir R, Pleiner T, Baleux F, Lortat-Jacob H, Coche-Guerente L, Richter RP Well-defined biomimetic surfaces to characterize glycosaminoglycan-mediated interactions on the molecular, supramolecular and cellular levels Biomaterials 35 8903-8915, 2014
Richter RP, Rodenhausen KB, Eisele NB, Schubert M Coupling Spectroscopic Ellipsometry and Quartz Crystal Microbalance to Study Organic Films at the Solid-Liquid Interface, 2014
Eisele NB, Labokha AA, Frey S, Görlich D, Richter RP Cohesiveness tunes assembly and morphology of FG nucleoporin domain meshworks - Implications for nuclear pore permeability Biophysical Journal 105 1860-1870, 2013
Baranova NS, Foulcer SJ, Briggs DC, Tilakaratna V, Enghild JJ, Milner CM, Day AJ, Richter RP Inter-α-inhibitor impairs TSG-6-induced hyaluronan cross-linking Journal of Biological Chemistry 288 29642-29653, 2013
Lopez-Rodriguez E, Cruz A, Richter RP, Taeusch HW, Pérez-Gil J Transient exposure of pulmonary surfactant to hyaluronan promotes structural and compositional transformations into a highly active state Journal of Biological Chemistry 288 29872-29881, 2013
Evans SF, Docheva D, Bernecker A, Colnot C, Richter RP, Knothe Tate ML Solid-supported lipid bilayers to drive stem cell fate and tissue architecture using periosteum derived progenitor cells Biomaterials 34 1878-1887, 2013
Elena L-R, Cruz A, Richter RP, Taeusch HW, Perez-Gil J Pre-Exposure of Pulmonary Surfactant to Hyaluronic Acid Alters its Structure and Interfacial Properties, 2013
Eisele NB, Labokha A, Frey S, Goerlich D, Richter RP The Supramolecular Assembly of Intrinsically Disordered Nucleoporin Domains is Tuned by Inter-Chain Interactions, 2013
Eisele NB, Andersson FI, Frey S, Richter RP Viscoelasticity of thin biomolecular films: A case study on nucleoporin phenylalanine-glycine repeats grafted to a histidine-tag capturing QCM-D sensor Biomacromolecules 13 2322-2332, 2012
Attili S, Borisov OV, Richter RP Films of end-grafted hyaluronan are a prototype of a brush of a strongly charged, semiflexible polyelectrolyte with intrinsic excluded volume Biomacromolecules 13 1466-1477, 2012
Attili S, Richter RP Combining colloidal probe atomic force and reflection interference contrast microscopy to study the compressive mechanics of hyaluronan brushes Langmuir 28 3206-3216, 2012
Attili S, Richter RP Compressive Mechanics of Hyaluronan Brushes - A Study with a Combined Colloidal Probe AFM/RICM Setup, 2012
Reviakine I, Johannsmann D, Richter RP Hearing what you cannot see and visualizing what you hear: Interpreting quartz crystal microbalance data from solvated interfaces Analytical Chemistry 83 8838-8848, 2011
Baranova NS, Attili S, Wolny PM, Richter RP The sweet coat of living cells - From supramolecular structure and dynamics to biological function International Journal of Materials Research 102 903-905, 2011
Baranova NS, Nilebäck E, Haller FM, Briggs DC, Svedhem S, Day AJ, Richter RP The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan-induced TSG-6 oligomers Journal of Biological Chemistry 286 25675-25686, 2011
Iturri Ramos JJ, Stahl S, Richter RP, Moya SE Water content and buildup of poly(diallyldimethylammonium chloride)/poly(sodium 4-styrenesulfonate) and poly(allylamine hydrochloride)/poly(sodium 4-styrenesulfonate) polyelectrolyte multilayers studied by an in situ combination of a quartz crystal microbalance with dissipation monitoring and spectroscopic ellipsometry Macromolecules 43 9063-9070, 2010
Carton I, Malinina L, Richter RP Dynamic modulation of the glycosphingolipid content in supported lipid bilayers by glycolipid transfer protein Biophysical Journal 99 2947-2956, 2010
Wolny PM, Banerji S, Gounou C, Brisson AR, Day AJ, Jackson DG, Richter RP Analysis of CD44-hyaluronan interactions in an artificial membrane system: Insights into the distinct binding properties of high and low molecular weight hyaluronan Journal of Biological Chemistry 285 30170-30180, 2010
Eisele NB, Frey S, Piehler J, Görlich D, Richter RP Ultrathin nucleoporin phenylalanine-glycine repeat films and their interaction with nuclear transport receptors EMBO Reports 11 366-372, 2010
Johannsmann D, Reviakine I, Richter RP Dissipation in films of adsorbed nanospheres studied by quartz crystal microbalance (QCM) Analytical Chemistry 81 8167-8176, 2009
Edvardsson M, Svedhem S, Wang G, Richter R, Rodahl M, Kasemo B QCM-D and reflectometry instrument: Applications to supported lipid structures and their biomolecular interactions Analytical Chemistry 81 349-361, 2009
Bingen P, Wang G, Steinmetz NF, Rodahl M, Richter RP Solvation effects in the quartz crystal microbalance with dissipation monitoring response to biomolecular adsorption. A phenomenological approach Analytical Chemistry 80 8880-8890, 2008
Tutus M, Rossetti FF, Schneck E, Fragneto G, Förster F, Richter R, Nawroth T, Tanaka M Orientation-selective incorporation of transmembrane F0F1 ATP synthase complex from micrococcus luteus in polymer-supported membranes Macromolecular Bioscience 8 1034-1043, 2008
Steinmetz NF, Bock E, Richter RP, Spatz JP, Lomonossoff GP, Evans DJ Assembly of multilayer arrays of viral nanoparticles via biospecific recognition: A quartz crystal microbalance with dissipation monitoring study Biomacromolecules 9 456-462, 2008
Richter RP, Hock KK, Burkhartsmeyer J, Boehm H, Bingen P, Wang G, Steinmetz NF, Evans DJ, Spatz JP Membrane-grafted hyaluronan films: A well-defined model system of glycoconjugate cell coats Journal of the American Chemical Society 129 5306-5307, 2007
Frey S, Richter RP, Görlich D FG-rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties Science 314 815-817, 2006
Solon J, Streicher P, Richter R, Brochard-Wyart F, Bassereau P Vesicles surfing on a lipid bilayer: Self-induced haptotactic motion Proceedings of the National Academy of Sciences of the United States of America 103 12382-12387, 2006
Richter RP, Him JLK, Tessier B, Tessier C, Brisson AR On the kinetics of adsorption and two-dimensional self-assembly of annexin A5 on supported lipid bilayers Biophysical Journal 89 3372-3385, 2005
Su X, Zong Y, Richter R, Knoll W Enzyme immobilization on poly(ethylene-co-acrylic acid) films studied by quartz crystal microbalance with dissipation monitoring Journal of Colloid and Interface Science 287 35-42, 2005
Richter RP, Brisson AR Following the formation of supported lipid bilayers on Mica: A study combining AFM, QCM-D, and ellipsometry Biophysical Journal 88 3422-3433, 2005
Hermens WT, Beneš M, Richter R, Speijer H Effects of flow on solute exchange between fluids and supported biosurfaces Biotechnology and Applied Biochemistry 39 277-284, 2004
Richter R, Mukhopadhyay A, Brisson A Pathways of lipid vesicle deposition on solid surfaces: a combined QCM-D and AFM study. Biophysical journal 85 3035-3047, 2003
Andersson J, Larsson R, Richter R, Ekdahl KN, Nilsson B Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation. Biomaterials 22 2435-2443, 2001