Ferrari L, Stucchi R, Konstantoulea K, van der Kamp G, Kos R, Geerts WJC, van Bezouwen LS, Förster FG, Altelaar M, Hoogenraad CC, Rüdiger SGD
Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
Nat Commun. 2020 11:571 Link
This paper describes a new molecular concept for aberrant interaction of neurotoxic fibrils. We identify pi-stacking as molecular mechanism for fibrils to specifically attract a specific subset of disordered protein. This offers a molecular reasoning for potential toxicity of fibrils in diseases such as Alzheimer.
Morán Luengo T, Kityk R, Mayer MP, Rüdiger SGD
Hsp90 breaks the deadlock of the Hsp70 chaperone system.
Mol Cell. 2018 70:545-552 (cover story). Link
This paper describes how chaperones can fold proteins. It shows that, contrary to expectation, Hsp70 at molecular level blocks folding, by constant and fast rebinding, effectively preventing protein folding at physiological concentrations. It is Hsp90 that breaks this vicious circle by offering a less hydrophobic binding site, which allows the protein to reach the native state. Based on biochemical folding assays, we provide a new paradigm how these chaperones ensure high folding yields without affecting the folding path. Thus, our results provide a consistent link between the chaperone paradigm and the Anfinsen concept that the primary structure determines the three-dimensional fold of a protein.
This paper was selected for the front cover.
Anvarian Z, Nojima H, van Kappel EC, Madl T, Spit M, Viertler M, Jordens I, Low TY, van Scherpenzeel R, Kuper I, Richter K, Heck AJR, Boelens R, Vincent JP, Rüdiger SGD, Maurice MM.
Axin cancer mutants form nano-aggregates to rewire the Wnt signaling network.
Nature Struct Mol Biol. 2016 23:324-32. Link
This publication describes the key result of the joint “High Potential” project with Madelon Maurice. Our findings established a paradigm for misregulation of signaling in cancer and show that targeting aggregation-prone stretches in mutated scaffolds holds attractive potential for cancer treatment. This study nailed an important biological question by using a multidisciplinary set of techniques, ranging from atomics resolution to living animal, including spectroscopy (fluorescence, CD and NMR), SAXS, mass spectrometry, cell culture, signalling assays, microscopy and drosophila genetics. The mutant, destabilised Axin, gained novel functions by forming non-amyloid nanometer-scale aggregates, which rewire the Axin interactome. Importantly, tumour suppressor activity of the Axin cancer mutant is rescued by preventing aggregation of a single, non-conserved segment.
Karagöz GE, Duarte AMS, Akoury E, Ippel H, Biernat J, Morán Luengo T, Radli M, Didenko T, Nordhues BA, Veprintsev DB, Dickey CA, Mandelkow E, Zweckstetter M, Boelens R, Madl T, Rüdiger SGD.
Hsp90-Tau complex reveals molecular basis for specificity in chaperone action.
Cell. 2014 156:963-974. Link
This is a key publication that turned the direction of my lab towards proteostasis control in neurobiology and neurodegenerative diseases by linking Hsp90 and Tau. It is the result of the previous 9 years of work on the Hsp90 research line in my group. This paper provided several important conceptional advances: (i) We localised the substrate binding region of Hsp90; (ii) we found that the binding principle of Hsp90 relies on a spreading of numerous contacts over a large surface; (iii) we characterised the disordered Tau protein as bona fide Hsp90 client; (iv) we identified the principles that allow intrinsically disordered proteins to become Hsp90 clients; (iv) we proposed a model that explains the timing of chaperone action in the Cell.
Karagöz GE, Duarte AMS, Ippel H, Uetrecht C, Sinnige T, van Rosmalen M, Hausmann J, Heck AJR, Boelens R, Rüdiger SGD.
N-terminal domain of human Hsp90 triggers binding to the cochaperone p23.
Proc Natl Acad Sci U S A. 2011 108:580-5. Link
This study established the technology that provided me with a competitive advantage in the field, the ability to monitor human Hsp90 by NMR. Strikingly, we found that the complex of Hsp90 with its co-chaperone p23 becomes asymmetric despite symmetric stoichiometry. This has interesting implication for understanding the molecular mechanism.
Rüdiger SGD, Germeroth L, Schneider-Mergener J, Bukau B.
Substrate specificity of the DnaK chaperone determined by screening cellulose bound peptide libraries.
EMBO J. 1997 16:1501-7. Link
This paper is the most significant from my time with Bernd Bukau. It is my most cited paper (>600 citations). This paper defined the molecular basis for substrate recognition of the Hsp70 chaperone family. I established an algorithm to predict binding sites of a major chaperone class in substrate proteins. In the course of this study, I invented a novel detection method to use peptide libraries, which is still widely used.