Person: Michaels, Thomas
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Michaels
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Thomas
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Michaels, Thomas
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Publication Direct Observation of Oligomerization by Single Molecule Fluorescence Reveals a Multistep Aggregation Mechanism for the Yeast Prion Protein Ure2(American Chemical Society, 2018) Yang, Jie; Dear, Alexander J.; Michaels, Thomas; Dobson, Christopher M.; Knowles, Tuomas P. J.; Wu, Si; Perrett, SarahThe self-assembly of polypeptides into amyloid structures is associated with a range of increasingly prevalent neurodegenerative diseases as well as with a select set of functional processes in biology. The phenomenon of self-assembly results in species with dramatically different sizes, from small oligomers to large fibrils; however, the kinetic relationship between these species is challenging to characterize. In the case of prion aggregates, these structures can self-replicate and act as infectious agents. Here we use single molecule spectroscopy to obtain quantitative information on the oligomer populations formed during aggregation of the yeast prion protein Ure2. Global analysis of the aggregation kinetics reveals the molecular mechanism underlying oligomer formation and depletion. Quantitative characterization indicates that the majority of Ure2 oligomers are relatively short-lived, and their rate of dissociation is much higher than their rate of conversion into growing fibrils. We identify an initial metastable oligomer, which can subsequently convert into a structurally distinct oligomer, which in turn converts into growing fibrils. We also show that fragmentation is responsible for the autocatalytic self-replication of Ure2 fibrils, but that preformed fibrils do not promote oligomer formation, indicating that secondary nucleation of the type observed for peptides and proteins associated with neurodegenerative disease does not occur at a significant rate for Ure2. These results establish a framework for elucidating the temporal and causal relationship between oligomers and larger fibrillar species in amyloid forming systems, and provide insights into why functional amyloid systems are not toxic to their host organisms.Publication Dynamics of Oligomer Populations Formed During the Aggregation of Alzheimer’s Aβ42 Peptide(Cold Spring Harbor Laboratory, 2020-04-13) Michaels, Thomas; Saric, Andela; Curk, Samo; Bernfur, Katja; Arosio, Paolo; Meisl, Georg; Dear, Alexander J; Cohen, Samuel I A; Dobson, Christopher M; Vendruscolo, Michele; Linse, Sara; Knowles, Tuomas P J; KnowlesOligomeric aggregates populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer's disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach combining theory, experiment, and simulation, we reveal in molecular detail the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we find that most Aβ42 oligomers dissociate to their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar species. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.Publication Kinetic constraints on self-assembly into closed supramolecular structures(Nature Publishing Group UK, 2017) Michaels, Thomas; Bellaiche, Mathias M. J.; Hagan, Michael F.; Knowles, Tuomas P. J.Many biological and synthetic systems exploit self-assembly to generate highly intricate closed supramolecular architectures, ranging from self-assembling cages to viral capsids. The fundamental design principles that control the structural determinants of the resulting assemblies are increasingly well-understood, but much less is known about the kinetics of such assembly phenomena and it remains a key challenge to elucidate how these systems can be engineered to assemble in an efficient manner and avoid kinetic trapping. We show here that simple scaling laws emerge from a set of kinetic equations describing the self-assembly of identical building blocks into closed supramolecular structures and that this scaling behavior provides general rules that determine efficient assembly in these systems. Using this framework, we uncover the existence of a narrow range of parameter space that supports efficient self-assembly and reveal that nature capitalizes on this behavior to direct the reliable assembly of viral capsids on biologically relevant timescales.Publication Budding-like division of all-aqueous emulsion droplets modulated by networks of protein nanofibrils(Nature Publishing Group UK, 2018) Song, Yang; Michaels, Thomas; Ma, Qingming; Liu, Zhou; Yuan, Hao; Takayama, Shuichi; Knowles, Tuomas P. J.; Shum, Ho CheungNetworks of natural protein nanofibrils, such as cytoskeletal filaments, control the shape and the division of cells, yet mimicking this functionality in a synthetic setting has proved challenging. Here, we demonstrate that artificial networks of protein nanofibrils can induce controlled deformation and division of all-aqueous emulsion droplets with budding-like morphologies. We show that this process is driven by the difference in the immersional wetting energy of the nanofibril network, and that both the size and the number of the daughter droplets formed during division can be controlled by modulating the fibril concentration and the chemical properties of the fibril network. Our results demonstrate a route for achieving biomimetic division with synthetic self-assembling fibrils and offer an engineered approach to regulate the morphology of protein gels.