Wälti Marielle A., Riek Roland, Orts Julien (2017), Fast NMR-Based Determination of the 3D Structure of the Binding Site of Protein-Ligand Complexes with Weak Affinity Binders, in Angewandte Chemie International Edition
, 56(19), 5208-5211.
Bibow Stefan, Polyhach Yevhen, Eichmann Cédric, Chi Celestine N, Kowal Julia, Albiez Stefan, McLeod Robert A, Stahlberg Henning, Jeschke Gunnar, Güntert Peter, Riek Roland (2017), Solution structure of discoidal high-density lipoprotein particles with a shortened apolipoprotein A-I, in Nature Structural & Molecular Biology
, 24(2), 187-193.
Eichmann Cédric, Bibow Stefan, Riek Roland (2017), α-Synuclein lipoprotein nanoparticles, in Nanotechnology Reviews
, 6(1), 105-110.
Ravotti Francesco, Wälti Marielle Aulikki, Güntert Peter, Riek Roland, Böckmann Anja, Meier Beat H. (2016), Solid-state NMR sequential assignment of an Amyloid-β(1–42) fibril polymorph, in Biomolecular NMR Assignments
, 10(2), 269-276.
Seuring Carolin, Gath Julia, Verasdonck Joeri, Cadalbert Riccardo, Rivier Jean, Böckmann Anja, Meier Beat H., Riek Roland (2016), Solid-state NMR sequential assignment of the β-endorphin peptide in its amyloid form, in Biomolecular NMR Assignments
, 10(2), 259-268.
Wälti Marielle Aulikki, Ravotti Francesco, Arai Hiromi, Glabe Charles G., Wall Joseph S., Böckmann Anja, Güntert Peter, Meier Beat H., Riek Roland (2016), Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril, in Proceedings of the National Academy of Sciences
, 113(34), E4976-E4984.
Eichmann Cédric, Tzitzilonis Christos, Kwiatkowski Witek, Riek Roland (2016), S-Sulfhydration of the Catalytic Cysteine in the Rhodanese Domain of YgaP is Complex Dynamic Process, in Matters (Zürich)
, y(c), 0-0.
Nespovitaya Nadezhda, Gath Julia, Barylyuk Konstantin, Seuring Carolin, Meier Beat H., Riek Roland (2016), Dynamic Assembly and Disassembly of Functional β-Endorphin Amyloid Fibrils, in Journal of the American Chemical Society
, 138(3), 846-856.
The presented proposal covers both main scientific projects of the Riek group. Project A: Structural Studies of Protein AggregatesProtein aggregation is a process in which identical proteins self-associate into imperfectly ordered macroscopic entities. Protein aggregates are in generally composed of a ß-sheet-rich entity termed cross-ß-sheet structure. These highly ordered cross-ß-sheet containing aggregates, termed amyloids, are the pathological hallmarks of several diseases including Alzheimer’s, and Parkinson’s disease, but are also associated with functional states such as hormone storage in secretory granules in mammals. It is the aim of this continuing proposal to study protein aggregation from a structural point of view with a particular focus on the structural and mechanistic comparison between functional and disease-associated amyloid systems. Aim 1 is the 3D structure determination of Aß(1-42) fibrils associated with Alzheimer’s disease: While the mechanism of toxicity of Aß(1-42) is unknown, Aß(1-42) amyloid fibrils are a pathological hallmark of Alzheimer’s disease and appear to play a role in cell-to-cell transmission. It is the goal to elucidate a 3D structure of a physiological relevant Aß(1-42) amyloid amongst other techniques by quenched H/D exchange Nuclear Magnetic Resonance Spectroscopy (NMR) and solid state NMR (in collaboration with B. Meier, ETH). Aim 2 is the study of the phase-space of Aß(1-42): Aß(1-42) is able to from many structural polymorphs. It is the goal to study structurally the phase-space of Aß(1-42) aggregation by covering diverse physiological buffers with various biological additives, followed by the analysis of the potential polymorphs by structural techniques including solid state NMR (in collaboration with B. Meier) and quenched H/D exchange NMR.Aim 3 is the structure-activity relationship of hormone amyloids: In striking contrast to the disease-associated amyloids, there are also amyloids with native biological activities including hormones storage in secretory granules. It is the aim to investigate the 3D structures of amyloids of the hormone ß-endorphin and somatostatin by quenched H/D exchange and solid state NMR (in collaboration with B. Meier) and establish a relationship between amyloid structure and secretory granule formation and hormone release by biophysical studies in vitro.Aim 4 is the structural studies of a-synuclein nanodiscs: a-synuclein associated with Parkinson’s disease is able to form a lipid-bilayer filled nanodisc. It is the goal to study this eventually biologically relevant entity structurally by electron microscopy in collaboration with H. Stahlberg (Biozentrum, Basel), NMR, multi-angle light scattering, etc.Project B: Structural Studies of Membrane ProteinsIntegral membrane proteins constitute more than 20% of all the proteins in mammalian organisms. However, membrane protein structure determination is still a challenge attributed to the two main bottlenecks: protein preparation and structure determination. It is the attempt to solve the 3D structure of an engineered nanodisc, and the study of the ion dynamics in the prototypical potassium channel KcsA.Aim 5 is the 3D structure determination of a nanodisc: Lipid-bilayer filled nanodiscs are an appreciated tool to study membrane proteins in a well-defined lipid bilayer. It is the goal to determine the 3D structure of an engineered nanodisc by solution NMR and EPR (in collaboration with G. Jeschke, ETH).Aim 6 is the study of the ion kinetics of the potassium channel KcsA: There are 4 K+ binding sites in the filter of KcsA. It has been proposed that only two are occupied per time during action. By replacing the K+ ion by the ammonium ion, the ion kinetics can be studied eventually site-resolved by solution state NMR.