Universitätsstraße 1 40225 Düsseldorf
The aggregation of proteins into amyloid fibril deposits is a pathological feature of various diseases, including nearly every major neurodegenerative disease such as Alzheimer and Parkinson. We are interested in the mechanism of amyloid formation, and investigate how it can be modulated. For this purpose, we employ a wide range of techniques in the area of biophysics, biochemistry, and molecular biology.
- Mechanism of amyloid formation
Amyloid formation is a multi-step reaction, characterized by the presence of diverse transient oligomeric states and multiple fibril polymorphs of distinct structure. We take a detailed look at the individual reaction steps and species. For example, we use TIRF microscopy to follow fibril elongation in real-time, we test the stability of oligomers by fluorescent reporters, and we investigate amyloid fibril structure by state-of-the-art structural biology techniques.
- Structural motifs in amyloidogenic intrinsically disordered proteins
Several disease-related aggregating proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs lack a defined globular structure, but can transiently adopt preferred conformations. We have identified β-hairpin motifs in amyloid-β (Aβ, associated with Alzheimer disease), α-synuclein (associated with Parkinson disease), and islet amyloid polypeptide (IAPP, associated with type 2 diabetes), which are established upon binding to engineered binding proteins. We determine the impact of such motifs on the aggregation reaction and on molecular recognition of amyloidogenic IDPs.
- Inhibition of amyloid formation
We investigate inhibitory effects on amyloid formation, including those of naturally occurring protein modifications. We generate small binding proteins, termed beta-wrapins, with affinities for α-synuclein, IAPP, and Aβ. Beta-wrapins inhibit aggregation and toxicity of the target proteins. Beta-wrapins act by interfering with the nucleation of aggregation and shifting the equilibrium to the monomeric, soluble state. We investigate if such agents are able to interfere with the pathological seeding and spreading of protein aggregates.
- Wördehoff M, Shaykhalishahi H, Groß L, Gremer L, Stoldt M, Buell AK, Willbold D, Hoyer W. Opposed effects of dityrosine formation in soluble and aggregated α-synuclein on fibril growth. J. Mol. Biol. 429, 3018-3030 (2017) PubMed
- Gremer L, Schölzel D, Schenk C, Reinartz E, Labahn J, Ravelli RB, Tusche M, Lopez-Iglesias C, Hoyer W, Heise H, Willbold D, Schröder GF. Fibril structure of amyloid-ß(1-42) by cryoelectron microscopy. Science 358, 116-119 (2017) PubMed
- Mirecka EA, Feuerstein S, Gremer L, Schröder GF, Stoldt M, Willbold D, Hoyer W. β-Hairpin of islet amyloid polypeptide bound to an aggregation inhibitor. Sci. Rep. 6, 33474 (2016) PubMed
- Shaykhalishahi H, Gauhar A, Wördehoff MM, Grüning CS, Klein A, Bannach O, Stoldt M, Willbold D, Härd T, Hoyer W. Contact between the beta1 and beta2 segments of alpha-synuclein that inhibits amyloid formation. Angew. Chem. Int. Ed. 54, 8837-8840 (2015) PubMed
- Shaykhalishahi H, Mirecka EA, Gauhar A, Grüning CSR, Willbold D, Härd T, Stoldt M, Hoyer W. A beta-hairpin-binding protein for three different disease-related amyloidogenic proteins. ChemBioChem 16, 411-414 (2015) PubMed
- Grüning CS, Mirecka EA, Klein AN, Mandelkow E, Willbold D, Marino SF, Stoldt M, Hoyer W. Alternative conformations of the tau repeat domain in complex with an engineered binding protein. J. Biol. Chem. 289, 23209-23218 (2014) PubMed
- Mirecka EA, Shaykhalishahi H, Gauhar A, Akgül S, Lecher J, Willbold D, Stoldt M, Hoyer W. Sequestration of a beta-hairpin for control of alpha-synuclein aggregation. Angew. Chem. Int. Ed. 53, 4227-4230 (2014) PubMed
- Grüning CS, Klinker S, Wolff M, Schneider M, Toksöz K, Klein AN, Nagel-Steger L, Willbold D, Hoyer W. The off-rate of monomers dissociating from amyloid-beta protofibrils. J Biol Chem. 288, 37104-37111 (2013) PubMed
- Luheshi LM, Hoyer W, de Barros TP, van Dijk-Härd I, Brorsson AC, Macao B, Persson C, Crowther DC, Lomas DA, Ståhl S, Dobson CM, Härd T. Sequestration of the Abeta peptide prevents toxicity and promotes degradation in vivo. PLoS Biol. 8, e1000334 (2010) PubMed
- Hoyer W, Grönwall C, Jonsson A, Ståhl S, Härd T. Stabilization of a beta-hairpin in monomeric Alzheimer’s amyloid-beta peptide inhibits amyloid formation. Proc. Natl. Acad. Sci. USA 105, 5099-5104 (2008) PubMed