Structural, morphological, and functional diversity of amyloid oligomers

Breydo, Leonid; Uversky, Vladimir N.

doi:10.1016/j.febslet.2015.07.013

Cited by 163 publications

(164 citation statements)

References 183 publications

(250 reference statements)

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“…Amyloid cross-β structures are generic, stable folding patterns for polypeptides (Dobson, 2003), and have been proposed as early peptide structures on ancient Earth (Greenwald and Riek, 2012; Maury, 2009). Some amyloid fibrils can support function (Fowler et al, 2007), and some functional natural proteins such as the small heat shock proteins behave like amyloid oligomers (Breydo and Uversky, 2015), exchanging between multiple β-sheet-rich oligomeric states (Delbecq and Klevit, 2013; Haslbeck and Vierling, 2015). Amyloid oligomers can be highly cytotoxic, but toxicity varies considerably with oligomer size and structural features (Breydo and Uversky, 2015), so this danger may be avoidable.…”

Section: Discussionmentioning

confidence: 99%

Foldability of a Natural De Novo Evolved Protein

et al. 2017

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SUMMARY The de novo evolution of protein-coding genes from noncoding DNA is emerging as a source of molecular innovation in biology. Studies of random sequence libraries, however, suggest that young de novo proteins will not fold into compact, specific structures typical of native globular proteins. Here we show that Bsc4, a functional, natural de novo protein encoded by a gene that evolved recently from noncoding DNA in the yeast S. cerevisiae, folds to a partially specific three-dimensional structure. Bsc4 forms soluble, compact oligomers with high β-sheet content and a hydrophobic core, and undergoes cooperative, reversible denaturation. Bsc4 lacks a specific quaternary state, however, existing instead as a continuous distribution of oligomer sizes, and binds dyes indicative of amyloid oligomers or molten globules. The combination of native-like and non-native-like properties suggests a rudimentary fold that could potentially act as a functional intermediate in the emergence of new folded proteins de novo.

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Section: Discussionmentioning

confidence: 99%

Foldability of a Natural De Novo Evolved Protein

et al. 2017

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“…In parallel with assembling to insoluble end-stage fibrils, the disease proteins often accumulate toxic oligomers that expose "sticky" surfaces (hydrophobic amino acid residues and unpaired b-strands) (152). These features confer to the oligomers the ability to engage in aberrant interactions with multiple key cellular proteins (153,154).…”

Section: Research | Reviewmentioning

confidence: 99%

In vivo aspects of protein folding and quality control

Balchin

Hayer‐Hartl

Hartl

2016

Science

1,183

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Most proteins must fold into unique three-dimensional structures to perform their biological functions. In the crowded cellular environment, newly synthesized proteins are at risk of misfolding and forming toxic aggregate species. To ensure efficient folding, different classes of molecular chaperones receive the nascent protein chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries is required to maintain protein homeostasis (proteostasis). The capacity of this proteostasis network declines during aging, facilitating neurodegeneration and other chronic diseases associated with protein aggregation. Understanding the proteostasis network holds the promise of identifying targets for pharmacological intervention in these pathologies.

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“…Misfolding and aggregation of polypeptides and proteins is a central pathological and biochemical event shared by many neurodegenerative maladies such as Alzheimer's, Parkinson's and other diseases [1,2]. Oligomeric forms of Aβ peptides are highly neurotoxic, are believed to play an important causal role in the AD pathogenesis and their levels correlate strongly with AD progression [3,4].…”

Section: Introductionmentioning

confidence: 99%