Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

Foley, Joseph; Hill, Shannon E.; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Muschol, Martin

doi:10.1063/1.4811343

Cited by 26 publications

(81 citation statements)

References 57 publications

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“… 19 − 21 Infrared spectroscopy from Aβ and lysozyme oligomers suggests that these oligomers form antiparallel β-sheets in contrast to the parallel β-sheet structure of their rigid fibril counterparts. 17 , 22 , 23 This structure is reminiscent of β-barrels and is consistent with high-resolution oligomer structures obtained from amyloidogenic model peptides via X-ray diffraction. 24 , 25 …”

Section: Introductionsupporting

confidence: 81%

Stable, Metastable, and Kinetically Trapped Amyloid Aggregate Phases

et al. 2014

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Self-assembly of proteins into amyloid fibrils plays a key role in a multitude of human disorders that range from Alzheimer’s disease to type II diabetes. Compact oligomeric species, observed early during amyloid formation, are reported as the molecular entities responsible for the toxic effects of amyloid self-assembly. However, the relation between early-stage oligomeric aggregates and late-stage rigid fibrils, which are the hallmark structure of amyloid plaques, has remained unclear. We show that these different structures occupy well-defined regions in a peculiar phase diagram. Lysozyme amyloid oligomers and their curvilinear fibrils only form after they cross a salt and protein concentration-dependent threshold. We also determine a boundary for the onset of amyloid oligomer precipitation. The oligomeric aggregates are structurally distinct from rigid fibrils and are metastable against nucleation and growth of rigid fibrils. These experimentally determined boundaries match well with colloidal model predictions that account for salt-modulated charge repulsion. The model also incorporates the metastable and kinetic character of oligomer phases. Similarities and differences of amyloid oligomer assembly to metastable liquid–liquid phase separation of proteins and to surfactant aggregation are discussed.

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Section: Introductionsupporting

confidence: 81%

Stable, Metastable, and Kinetically Trapped Amyloid Aggregate Phases

et al. 2014

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“…28 Figure 6a displays AFM images of lysozyme oligomers used for seeding and the morphologies of the resulting aggregates formed after incubation with native lysozyme at 37 °C for 5 days and 3 weeks, respectively. Following incubation, increasing numbers of highly flexible protofibrils appeared that tended to fold onto themselves upon deposition onto mica surfaces.…”

Section: Resultsmentioning

confidence: 99%

Amyloid Oligomers and Protofibrils, but Not Filaments, Self-Replicate from Native Lysozyme

2014

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Self-assembly of amyloid fibrils is the molecular mechanism best known for its connection with debilitating human disorders such as Alzheimer’s disease but is also associated with various functional cellular responses. There is increasing evidence that amyloid formation proceeds along two distinct assembly pathways involving either globular oligomers and protofibrils or rigid monomeric filaments. Oligomers, in particular, have been implicated as the dominant molecular species responsible for pathogenesis. Yet the molecular mechanisms regulating their self-assembly have remained elusive. Here we show that oligomers/protofibrils and monomeric filaments, formed along distinct assembly pathways, display critical differences in their ability to template amyloid growth at physiological vs denaturing temperatures. At physiological temperatures, amyloid filaments remained stable but could not seed growth of native monomers. In contrast, oligomers and protofibrils not only remained intact but were capable of self-replication using native monomers as the substrate. Kinetic data further suggested that this prion-like growth mode of oligomers/protofibrils involved two distinct activities operating orthogonal from each other: autocatalytic self-replication of oligomers from native monomers and nucleated polymerization of oligomers into protofibrils. The environmental changes to stability and templating competence of these different amyloid species in different environments are likely to be important for understanding the molecular mechanisms underlying both pathogenic and functional amyloid self-assembly.

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“…52,53 We have observed a similar proportionality associated with amyloid fibril growth by hen egg-white lysozyme. 54 We argued there that the similarity of these 2 kinetics signals indicates that the underlying growth kinetics are dominated by the rate of new aggregate formation over the rate for growth/elongation of existing aggregates. PLE spherulite growth kinetics therefore replicates that feature of amyloid fibril growth, as well.…”

Section: Structural Organization Of Ple Spherulitesmentioning

confidence: 95%

Collapsed state of polyglutamic acid results in amyloid spherulite formation

Stehli

Mulaj

Miti

et al. 2015

Intrinsically Disordered Proteins

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Self-assembly of proteins and peptides into amyloid fibrils involves multiple distinct intermediates and late-stage fibrillar polymorphs. Understanding the conditions and mechanisms that promote the formation of one type of intermediate and polymorph over the other represents a fundamental challenge. Answers to this question are also of immediate biomedical relevance since different amyloid aggregate species have been shown to have distinct pathogenic potencies. One amyloid polymorph that has received comparatively little attention are amyloid spherulites. Here we report that self-assembly of the intrinsically disordered polymer poly(L-glutamic) acid (PLE) can generate amyloid spherulites. We characterize spherulite growth kinetics, as well as the morphological, optical and tinctorial features of this amyloid polymorph previously unreported for PLE. We find that PLE spherulites share both tinctorial and structural characteristics with their amyloid fibril counterparts. Differences in PLE's molecular weight, polydispersity or chemistry could not explain the selective propensity toward either fibril or spherulite formation. Instead, we provide evidence that PLE polymers can exist in either a collapsed globule or an extended random coil conformation. The collapsed globule consistently produces spherulites while the extended coil assembles into disordered fibril bundles. This results suggests that these 2 PLE conformers directly affect the morphology of the resulting macroscopic amyloid assembly.

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Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

Cited by 26 publications

References 57 publications

Stable, Metastable, and Kinetically Trapped Amyloid Aggregate Phases

Stable, Metastable, and Kinetically Trapped Amyloid Aggregate Phases

Amyloid Oligomers and Protofibrils, but Not Filaments, Self-Replicate from Native Lysozyme

Collapsed state of polyglutamic acid results in amyloid spherulite formation

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