Folding into a β-Hairpin Can Prevent Amyloid Fibril Formation

Hosia, Waltteri; Bark, Niklas; Лиепиньш, Э. Э.; Tjernberg, Agneta; Persson, Bengt; Hallén, Dan; Thyberg, Johan; Johansson, Jan; Tjernberg, Lars O.

doi:10.1021/bi036248t

Cited by 28 publications

(21 citation statements)

References 29 publications

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“…But if the β-hairpin structures are not easily able to ‘open up’ to form extended β-strands then this will have the effect of slowing fibrillization kinetics. Stabilization of β-hairpin structure has continually been found to inhibit the formation of amyloid fibrils whilst promoting oligomer formation in Aβ [76], [77], [78], [79], [80], polyglutamine peptides [81] and the short amyloidogenic peptide KFFE [82]. Moreover, peptides designed to form β-hairpin structure can interfere with amylin and α-synuclein fibrillization [83] and with Aβ aggregation [84].…”

Section: Discussionmentioning

confidence: 99%

β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

Gill

2014

PLoS ONE

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Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies.

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Section: Discussionmentioning

confidence: 99%

β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

Gill

2014

PLoS ONE

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“…The polypeptide sequence is KFFEAAAKKFFE (referred to hereafter as AAAK) and contains a 4-mer motif at either end with a hydrophobic region in the center designed to inhibit the formation of a ␤-turn (8). Motifs within the original peptide are found in the sequences of notable amyloidogenic peptides.…”

mentioning

confidence: 99%

Molecular basis for amyloid fibril formation and stability

Makin

Atkins²,

Sikorski³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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632

586

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The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 Å) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel ␤-sheets in a cross-␤ arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel ␤-sheets are zipped together by means of -bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid-lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils.x-ray diffraction ͉ side-chain packing ͉ structure ͉ -bonding ͉ ␤-sheet interaction

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“…Similar to isolated KFFE domains during their self-assembly, the three peptides we tested may assemble in an anti-parallel orientation, which may primarily be driven by electrostatic interactions between oppositely charged Lys and Glu residues from adjacent molecules [17,27]. However, the possibility of these three peptides to assemble in other orientations may not be completely excluded as discussed previously [19]. …”

Section: Resultsmentioning

confidence: 97%

“…π–π interactions between Phe residues in adjacent molecules may also promote aggregation of KFFE [17,18]. Results from previous studies suggest that the aforementioned physicochemical factors may play an important role in aggregation of peptides containing KFFE [17,19]. In our current study, we inserted several GS-rich sequences, which were carefully designed to display dissimilarity in length yet similarity in other physicochemical properties, between two identical KFFE domains.…”

Section: Introductionmentioning

confidence: 99%

Effects of Intramolecular Distance between Amyloidogenic Domains on Amyloid Aggregation

Kim

2012

IJMS

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Peptide/protein aggregation is implicated in many amyloid diseases. Some amyloidogenic peptides/proteins, such as those implicated in Alzheimer’s and Parkinson’s diseases, contain multiple amyloidogenic domains connected by “linker” sequences displaying high propensities to form turn structures. Recent studies have demonstrated the importance of physicochemical properties of each amino acid contained in the polypeptide sequences in amyloid aggregation. However, effects on aggregation related to the intramolecular distance between amyloidogenic domains, which may be determined by a linker length, have yet to be examined. In the study presented here, we created peptides containing two copies of KFFE, a simple four-residue amyloidogenic domain, connected by GS-rich linker sequences with different lengths yet similar physicochemical properties. Our experimental results indicate that aggregation occurred most rapidly when KFFE domains were connected by a linker of an intermediate length. Our experimental findings were consistent with estimated entropic contribution of a linker length toward formation of (partially) structured intermediates on the aggregation pathway. Moreover, inclusion of a relatively short linker was found to inhibit formation of aggregates with mature fibril morphology. When the results are assimilated, our study demonstrates that intramolecular distance between amyloidogenic domains is an important yet overlooked factor affecting amyloid aggregation.

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Folding into a β-Hairpin Can Prevent Amyloid Fibril Formation

Cited by 28 publications

References 29 publications

β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

Molecular basis for amyloid fibril formation and stability

Effects of Intramolecular Distance between Amyloidogenic Domains on Amyloid Aggregation

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