Mutations and Seeding of Amylin Fibril-Like Oligomers

Bernhardt, Nathan; Berhanu, Workalemahu M.; Hansmann, Ulrich H. E.

doi:10.1021/jp409777p

Cited by 29 publications

(40 citation statements)

References 64 publications

(141 reference statements)

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“…In the Y37L mutants, the lack of tyrosine-specific interactions causes significant larger flexibility of the C terminal region than in the wild-type fibril. This hinders elongation of the Y37L mutant fibril leading to the longer lag times during aggregation that are observed in experiments for this mutant (Bernhardt, Berhanu, & Hansmann, 2013).…”

Section: Amyloid Aggregation and Cross Seedingmentioning

confidence: 88%

Stability of Amyloid Oligomers

Berhanu¹,

Hansmann²

2014

Advances in Protein Chemistry and Structural Biology

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Section: Amyloid Aggregation and Cross Seedingmentioning

confidence: 88%

Stability of Amyloid Oligomers

Berhanu¹,

Hansmann²

2014

Advances in Protein Chemistry and Structural Biology

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“…This could be either a consequence of the low solubility or the tight cross-β-structure of the amyloid fibrils [56]. Furthermore, the presence of amyloid fibrils is known to have a strong promoting effect on the aggregation process [57–58], whereby nucleation, together with the unfavorable structure could conceal the effect of phosphorylation. Thus, a further proof was the chemically phosphorylated peptide P C KFM6 which completely lost its ability to undergo a conformational transition and remains random coil even at higher concentrations.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of peptide aggregation by means of enzymatic phosphorylation

Folmert¹,

Broncel²,

Berlepsch³

et al. 2016

Beilstein J. Org. Chem.

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As is the case in numerous natural processes, enzymatic phosphorylation can be used in the laboratory to influence the conformational populations of proteins. In nature, this information is used for signal transduction or energy transfer, but has also been shown to play an important role in many diseases like tauopathies or diabetes. With the goal of determining the effect of phosphorylation on amyloid fibril formation, we designed a model peptide which combines structural characteristics of α-helical coiled-coils and β-sheets in one sequence. This peptide undergoes a conformational transition from soluble structures into insoluble amyloid fibrils over time and under physiological conditions and contains a recognition motif for PKA (cAMP-dependent protein kinase) that enables enzymatic phosphorylation. We have analyzed the pathway of amyloid formation and the influence of enzymatic phosphorylation on the different states along the conformational transition from random-coil to β-sheet-rich oligomers to protofilaments and on to insoluble amyloid fibrils, and we found a remarkable directing effect from β-sheet-rich structures to unfolded structures in the initial growth phase, in which small oligomers and protofilaments prevail if the peptide is phosphorylated.

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“…Previous results reported that six polymorphic structures were categorized depending on the interfacing β‐strands, that is, whether the strands included the N‐terminal or C‐terminal residue, or were in the β‐strand direction along to fibril axis. Therefore, we constructed six polymorphic Aβ pair structures per each model and length type according to previous studies . The six structures were CCnn, CCun, NNnn, NNun, NCnn, and NCun (Fig.…”

Section: Methodsmentioning

confidence: 99%

Structural analysis of oligomeric and protofibrillar Aβ amyloid pair structures considering F20L mutation effects using molecular dynamics simulations

et al. 2017

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Aβ amyloid proteins are involved in neuro-degenerative diseases such as Alzheimer's, Parkinson's, and so forth. Because of its structurally stable feature under physiological conditions, Aβ amyloid protein disrupts the normal cell function. Because of these concerns, understanding the structural feature of Aβ amyloid protein in detail is crucial. There have been some efforts on lowering the structural stabilities of Aβ amyloid fibrils by decreasing the aromatic residues characteristic and hydrophobic effect. Yet, there is a lack of understanding of Aβ amyloid pair structures considering those effects. In this study, we provide the structural characteristics of wildtype (WT) and phenylalanine residue mutation to leucine (F20L) Aβ amyloid pair structures using molecular dynamics simulation in detail. We also considered the polymorphic feature of F20L and WT Aβ pair amyloids based on the facing β-strand directions between the amyloid pairs. As a result, we were able to observe the varying effects of mutation, polymorphism, and protofibril lengths on the structural stability of pair amyloids. Furthermore, we have also found that opposite structural stability exists on a certain polymorphic Aβ pair amyloids depending on its oligomeric or protofibrillar state, which can be helpful for understanding the amyloid growth mechanism via repetitive fragmentation and elongation mechanism. Proteins 2017; 85:580-592. © 2016 Wiley Periodicals, Inc.

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Mutations and Seeding of Amylin Fibril-Like Oligomers

Cited by 29 publications

References 64 publications

Stability of Amyloid Oligomers

Stability of Amyloid Oligomers

Inhibition of peptide aggregation by means of enzymatic phosphorylation

Structural analysis of oligomeric and protofibrillar Aβ amyloid pair structures considering F20L mutation effects using molecular dynamics simulations

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