Random Coils, β-Sheet Ribbons, and α-Helical Fibers:  One Peptide Adopting Three Different Secondary Structures at Will

Pagel, Kevin; Wagner, Sara C.; Samedov, Kerim; Berlepsch, Hans von; Böttcher, Christoph; Koksch, Beate

doi:10.1021/ja057450h

Cited by 110 publications

(111 citation statements)

References 10 publications

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“…This observation suggests that an external driving force will be needed in vivo. The α-helix to β-sheet (α-to-β) transition in other coiled coils has been shown to be enhanced by mechanical force (21,22), high temperature (23), pH change (24), and high protein concentration (25). A mechanical force-induced α-to-β transition has been observed in fibrin (22), collagen, and vimentin (26).…”

Section: α-Helix To β-Sheet Transition In a Coiled Coil Is Promoted Bmentioning

confidence: 97%

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Chen

Zheng

Wolynes

2016

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

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Aplysia cytoplasmic polyadenylation element binding (CPEB) protein, a translational regulator that recruits mRNAs and facilitates translation, has been shown to be a key component in the formation of long-term memory. Experimental data show that CPEB exists in at least a low-molecular weight coiled-coil oligomeric form and an amyloid fiber form involving the Q-rich domain (CPEB-Q). Using a coarse-grained energy landscape model, we predict the structures of the low-molecular weight oligomeric form and the dynamics of their transitions to the β-form. Up to the decamer, the oligomeric structures are predicted to be coiled coils. Free energy profiles confirm that the coiled coil is the most stable form for dimers and trimers. The structural transition from α to β is shown to be concentration dependent, with the transition barrier decreasing with increased concentration. We observe that a mechanical pulling force can facilitate the α-helix to β-sheet (α-to-β) transition by lowering the free energy barrier between the two forms. Interactome analysis of the CPEB protein suggests that its interactions with the cytoskeleton could provide the necessary mechanical force. We propose that, by exerting mechanical forces on CPEB oligomers, an active cytoskeleton can facilitate fiber formation. This mechanical catalysis makes possible a positive feedback loop that would help localize the formation of CPEB fibers to active synapse areas and mark those synapses for forming a long-term memory after the prion form is established. The functional role of the CPEB helical oligomers in this mechanism carries with it implications for targeting such species in neurodegenerative diseases.long-term memory | mechanical prion | protein aggregation | Q-rich protein I t is widely believed that learning involves the modification in number, strength, and structure of specific localized synaptic connections. Although short-term memory formation occurs without protein synthesis, establishing long-term memory (LTM) involves protein synthesis localized at the synapse area, thus requiring a stable translational regulatory system that activates mRNA and protein synthesis in the synapse (1-3). It has long been recognized that the relatively short half-life of most proteins in eukaryotic cells (4) poses questions about the long timescales over which memories can be retained. It has been suggested that forming a very stable prion could provide a mechanism for achieving memory longevity (5, 6). An excellent candidate species has emerged from the works of Kandel and coworkers (1-3) and Lindquist and coworker (6) on cytoplasmic polyadenylation element binding (CPEB). It has been established, in Aplysia, that Aplysia cytoplasmic polyadenylation element binding (ApCPEB) activates mRNA and mediates synaptic protein synthesis for at least 72 h and that it does so by taking on a functional prion-like form (3, 7). Forming the prion is, thus, a key element in LTM formation and maintenance.Prions were first proposed as protein-only infectious particles causing Creu...

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Section: α-Helix To β-Sheet Transition In a Coiled Coil Is Promoted Bmentioning

confidence: 97%

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Chen

Zheng

Wolynes

2016

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

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“…Previous studies by our group have shown that incorporation of three b-sheet preferring valine residues at the b, c, and f positions of the heptad repeat sufficiently enhance the amyloid-formation propensity of a 26-residue coiled-coil peptide. [24,26] Thus, three valine residues were incorporated into the model peptides presented here to yield an inherent competition between a-helical coiled-coil folding and the b-sheet rich amyloid structure.…”

Section: Peptide Designmentioning

confidence: 99%

How Metal Ions Affect Amyloid Formation: Cu²⁺‐ and Zn²⁺‐Sensitive Peptides

et al. 2008

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The common feature of proteins involved in many neurodegenerative diseases is their ability to adopt at least two different stable conformations. The conformational transition that shifts the equilibrium from the functional, mostly partially alpha-helical structure, to the beta-sheet rich amyloid can be triggered by numerous factors, such as mutations in the primary structure or changes in the environment. We present a set of model peptides that, without changes in their primary structure, react in a predictable fashion in the presence of transition metal ions by adopting different conformations and aggregate morphologies. These de novo designed peptides strictly follow the characteristic heptad repeat of the alpha-helical coiled-coil structural motif. Furthermore, domains that favor beta-sheet formation have been incorporated to make the system prone to amyloid formation. As a third feature, histidine residues create sensitivity towards the presence of transition metal ions. CD spectroscopy, ThT fluorescence experiments, and transmission electron microscopy were used to characterize peptide conformation and aggregate morphology in the presence of Cu2+ and Zn2+. Furthermore, the binding geometry within peptide-Cu2+ complexes was characterized by electron paramagnetic resonance spectroscopy.

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“…[11,19,20] We have explored the a-helical coiled coil folding motif, which is very common in nature and has been extensively studied in recent years, proving its application as a reliable model system. [9,11,19,20,41] Furthermore, the design principles of coiled coils are very well understood, [21] and folding is based on oligomerization, which is also the foundation of amyloid formation. Coiled coils consist of at least two a-helices wrapped around each other in a slight superhelical twist.…”

Section: Introductionmentioning

confidence: 99%

How Post‐Translational Modifications Influence Amyloid Formation: A Systematic Study of Phosphorylation and Glycosylation in Model Peptides

Broncel

Falenski

Wagner

et al. 2010

Chemistry A European J

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A reciprocal relationship between phosphorylation and O-glycosylation has been reported for many cellular processes and human diseases. The accumulated evidence points to the significant role these post-translational modifications play in aggregation and fibril formation. Simplified peptide model systems provide a means for investigating the molecular changes associated with protein aggregation. In this study, by using an amyloid-forming model peptide, we show that phosphorylation and glycosylation can affect folding and aggregation kinetics differently. Incorporation of phosphoserines, regardless of their quantity and position, turned out to be most efficient in preventing amyloid formation, whereas O-glycosylation has a more subtle effect. The introduction of a single beta-galactose does not change the folding behavior of the model peptide, but does alter the aggregation kinetics in a site-specific manner. The presence of multiple galactose residues has an effect similar to that of phosphorylation.

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Random Coils, β-Sheet Ribbons, and α-Helical Fibers: One Peptide Adopting Three Different Secondary Structures at Will

Cited by 110 publications

References 10 publications

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

How Metal Ions Affect Amyloid Formation: Cu²⁺‐ and Zn²⁺‐Sensitive Peptides

How Post‐Translational Modifications Influence Amyloid Formation: A Systematic Study of Phosphorylation and Glycosylation in Model Peptides

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Random Coils, β-Sheet Ribbons, and α-Helical Fibers: One Peptide Adopting Three Different Secondary Structures at Will

Cited by 110 publications

References 10 publications

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

How Metal Ions Affect Amyloid Formation: Cu2+‐ and Zn2+‐Sensitive Peptides

How Post‐Translational Modifications Influence Amyloid Formation: A Systematic Study of Phosphorylation and Glycosylation in Model Peptides

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How Metal Ions Affect Amyloid Formation: Cu²⁺‐ and Zn²⁺‐Sensitive Peptides