Functional amyloid

Otzen, Daniel E.

doi:10.4161/pri.4.4.13676

Cited by 87 publications

(37 citation statements)

References 74 publications

(90 reference statements)

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“…Amyloid fibrils, including those from FapC, are highly resistant to acidic conditions [43], so increased fibril formation at low pH values could help provide a denser mesh of protective protein to shield the biofilm from harsh conditions. The EM of Pseudomonas is highly complex, however, so interactions between FapC and other matrix components—particularly charged macromolecules such as the exopolysaccharides Pel, Psl, and alginate, as well as extracellular DNA [44]—must be considered to fully elucidate the effect of pH on aggregation in vivo .…”

Section: Discussionmentioning

confidence: 99%

Protein Engineering Reveals Mechanisms of Functional Amyloid Formation in Pseudomonas aeruginosa Biofilms

Bleem

Christiansen

Madsen

et al. 2018

Journal of Molecular Biology

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Amyloids are typically associated with neurodegenerative diseases, but recent research demonstrates that several bacteria utilize functional amyloid fibrils to fortify the biofilm extracellular matrix and thereby resist antibiotic treatments. In Pseudomonas aeruginosa, these fibrils are composed predominantly of FapC, a protein with high-sequence conservation among the genera. Previous studies established FapC as the major amyloid subunit, but its mechanism of fibril formation in P. aeruginosa remained largely unexplored. Here, we examine the FapC sequence in greater detail through a combination of bioinformatics and protein engineering, and we identify specific motifs that are implicated in amyloid formation. Sequence regions of high evolutionary conservation tend to coincide with regions of high amyloid propensity, and mutation of amyloidogenic motifs to a designed, non-amyloidogenic motif suppresses fibril formation in a pH-dependent manner. We establish the particular significance of the third repeat motif in promoting fibril formation and also demonstrate emergence of soluble oligomer species early in the aggregation pathway. The insights reported here expand our understanding of the mechanism of amyloid polymerization in P. aeruginosa, laying the foundation for development of new amyloid inhibitors to combat recalcitrant biofilm infections.

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Section: Discussionmentioning

confidence: 99%

Protein Engineering Reveals Mechanisms of Functional Amyloid Formation in Pseudomonas aeruginosa Biofilms

Bleem

Christiansen

Madsen

et al. 2018

Journal of Molecular Biology

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“…Despite their similarity in structure, amyloid fibrils can be beneficial to the organism concerned, whereas for others amyloid formation is deleterious (Otzen, 2010). For each scenario, mechanisms have evolved that either facilitate assembly or protect against the accumulation of aggregation-competent proteins, depending on whether the fibrils are beneficial or not (Bucciantini et al., 2002; Otzen, 2010; Maji et al., 2009).…”

Section: Discussionmentioning

confidence: 99%

Visualization of Transient Protein-Protein Interactions that Promote or Inhibit Amyloid Assembly

et al. 2014

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SummaryIn the early stages of amyloid formation, heterogeneous populations of oligomeric species are generated, the affinity, specificity, and nature of which may promote, inhibit, or define the course of assembly. Despite the importance of the intermolecular interactions that initiate amyloid assembly, our understanding of these events remains poor. Here, using amyloidogenic and nonamyloidogenic variants of β2-microglobulin, we identify the interactions that inhibit or promote fibril formation in atomic detail. The results reveal that different outcomes of assembly result from biomolecular interactions involving similar surfaces. Specifically, inhibition occurs via rigid body docking of monomers in a head-to-head orientation to form kinetically trapped dimers. By contrast, the promotion of fibrillation involves relatively weak protein association in a similar orientation, which results in conformational changes in the initially nonfibrillogenic partner. The results highlight the complexity of interactions early in amyloid assembly and reveal atomic-level information about species barriers in amyloid formation.

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“…This fact provides a strong support to the hypothesis that the ability to form fibrils can be considered as inherent and generic characteristics of the polypeptide chain emerging from the physical and chemical properties of the polypeptide chain itself (Dobson, 2006). Moreover, there is growing evidence that in nature there is a wide variety of organisms that are able to take advantage of the controlled aggregation of specific proteins and peptides to generate fully functional structures for beneficial reasons (Fowler et al, 2007; Otzen, 2010). …”

Section: Introductionmentioning

confidence: 99%

Nanoscale Structure and Spectroscopic Probing of Aβ1-40 Fibril Bundle Formation

et al. 2016

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Amyloid plaques composed of fibrillar Amyloid-β (Aβ) are hallmarks of Alzheimer's disease. However, Aβ fibrils are morphologically heterogeneous. Conformation sensitive luminescent conjugated oligothiophenes (LCOs) are versatile tools for monitoring such fibril polymorphism in vivo and in vitro. Biophysical methods applied on in vitro generated Aβ fibrils, stained with LCOs with different binding and fluorescence properties, can be used to characterize the Aβ fibrillation in depth, far beyond that possible for in vivo generated amyloid plaques. In this study, in vitro fibrillation of the Aβ1-40 peptide was monitored by time-lapse transmission electron microscopy, LCO fluorescence, and atomic force microscopy. Differences in the LCO binding in combination with nanoscale imaging revealed that spectral variation correlated with fibrils transforming from solitary filaments (Ø~2.5 nm) into higher order bundled structures (Ø~5 nm). These detailed in vitro experiments can be used to derive data that reflects the heterogeneity of in vivo generated Aβ plaques observed by LCO fluorescence. Our work provides new structural basis for targeted drug design and molecular probe development for amyloid imaging.

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Functional amyloid

Cited by 87 publications

References 74 publications

Protein Engineering Reveals Mechanisms of Functional Amyloid Formation in Pseudomonas aeruginosa Biofilms

Protein Engineering Reveals Mechanisms of Functional Amyloid Formation in Pseudomonas aeruginosa Biofilms

Visualization of Transient Protein-Protein Interactions that Promote or Inhibit Amyloid Assembly

Nanoscale Structure and Spectroscopic Probing of Aβ1-40 Fibril Bundle Formation

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