Abstract
The formation of amyloid fibrils is a general class of protein self-assembly behaviour, which is associated with both functional biology and the development of a number of disorders, such as Alzheimer and Parkinson diseases. In this Review, we discuss how general physical concepts from the study of phase transitions can be used to illuminate the fundamental mechanisms of amyloid self-assembly. We summarize progress in the efforts to describe the essential biophysical features of amyloid self-assembly as a nucleation-and-growth process and discuss how master equation approaches can reveal the key molecular pathways underlying this process, including the role of secondary nucleation. Additionally, we outline how non-classical aspects of aggregate formation involving oligomers or biomolecular condensates have emerged, inspiring developments in understanding, modelling and modulating complex protein assembly pathways. Finally, we consider how these concepts can be applied to kinetics-based drug discovery and therapeutic design to develop treatments for protein aggregation diseases.
Key points
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Amyloid formation is a transition between the dilute solution phase of a protein and a solid β-sheet-rich aggregated phase that occurs through nucleation-and-growth processes.
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Uncontrolled formation of amyloid aggregates from normally soluble proteins is a general form of molecular malfunction.
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Kinetic analysis using master equation approaches reveals the fundamental molecular steps underpinning this transition.
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Processes such as secondary nucleation and the formation of on-pathway or off-pathway oligomers and liquid condensate intermediate states lead to a complex network of reaction pathways.
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Kinetic equations can be combined with control theory to modulate or curtail amyloid formation and optimize therapeutic strategies for protein aggregation diseases.
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Acknowledgements
The authors acknowledge support from the Institute for the Physics of Living Systems, University College London (T.C.T.M.), the Swedish Research Council (2015-00143) (S.L.), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) through the ERC grant PhysProt (agreement no. 337969) (T.P.J.K.), the BBSRC (T.P.J.K.), the Newman Foundation (T.P.J.K.) and the Wellcome Trust Collaborative Award 203249/Z/16/Z (T.P.J.K.). The authors thank C. Flandoli for help with illustrations.
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T.C.T.M. and D.Q. researched data for the article. All authors contributed substantially to discussion of the content. T.C.T.M. and D.Q. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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Glossary
- β-Sheet
-
Common protein secondary structures consisting of strands of amino acids arranged parallel or antiparallel to one another, connected laterally by hydrogen bonds to form a pleated sheet.
- Coarse-grained
-
In modelling complex systems or in renormalization, coarse-graining refers to the procedure in which two or more microscopic entities are replaced with a single entity to reduce the complexity or resolution of the model.
- Critical nuclei
-
The smallest growth-competent unit of the new phase in a nucleation process.
- Elongation
-
The addition of individual monomers to the ends of existing aggregates.
- Fragmentation
-
The breaking of fibrils at any location along their length, which gives rise to new fibrils in a way that depends solely on the existing aggregate concentration.
- Global fits
-
A fitting process in which kinetic aggregation curves at various initial monomer concentrations are fitted simultaneously to an integrated rate law using a single choice of rate parameters. This is to be distinguished from individual fits, in which each kinetic curve is fitted individually using different choices of rate parameters.
- Half-time
-
The time required for half of the initial monomer concentration to convert into fibrils.
- Hydrophobic effect
-
The thermodynamic tendency to reduce the surface area of nonpolar molecules exposed to an aqueous solvent gives rise to hydrophobic forces.
- Lag phase
-
A period of time with a negligible macroscopic aggregate signal at the beginning of an aggregation experiment.
- Microphase separation
-
The spontaneous formation of microscopic phase-separated domains from block copolymers with chemically incompatible components.
- Monomers
-
A basic assembly unit. Monomer building blocks can also be protein complexes (for example, dimers and trimers) rather than just individual proteins.
- Monomer dissociation
-
The removal of monomers from the ends of fibrils.
- Nonspecific interaction
-
In molecular simulations, the interaction energy between two particles can depend on the particle type being modelled, for instance, electrostatic or hydrophobic interactions. Nonspecific interactions do not depend on the particle type and act as a generic attraction force between all particles.
- Nucleation
-
The first stage in the formation of a new phase of matter, which requires the formation of a small nucleus of the new structure before the new structure can grow.
- Oligomer
-
Microscopic clusters of proteins, each consisting of only a few monomer units. Unlike amyloid states, these are dynamic structures, which can readily dissociate back into the monomer state or convert into a fibrillar state through a structural change.
- Phase separation
-
The formation of a highly concentrated droplet phase that stably coexists within the surrounding more dilute phase.
- Polymorphism
-
The ability of closely related protein sequences to form distinctly different structures.
- Reactive flux
-
In a chemical reaction network, the temporal evolution of the population of a molecular species is controlled by processes that either produce the species or consume it. The number of molecules produced or consumed by each process per unit time is the flux into or out of that molecular state.
- Seeds
-
Pre-formed fibrils that are used to start an aggregation reaction.
- Spinodal decomposition
-
The spinodal region corresponds to points on the free energy landscape where arbitrarily small fluctuations in the density of a solute lead to a decrease in total free energy, and thus small fluctuations grow quickly over time and forming new phases as a result.
- Surface-catalysed secondary nucleation
-
A nucleation process in which the surface of existing fibrils acts as a template to catalyse the nucleation of new aggregates.
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Michaels, T.C.T., Qian, D., Šarić, A. et al. Amyloid formation as a protein phase transition. Nat Rev Phys 5, 379–397 (2023). https://doi.org/10.1038/s42254-023-00598-9
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DOI: https://doi.org/10.1038/s42254-023-00598-9
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