Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein

Ulamec, Sabine M.; Maya-Martinez, Roberto; Byrd, Emily J; Dewison, Katherine M.; Xu, Yong; Willis, Leon F.; Sobott, Frank; Heath, George R.; Oosten-Hawle, Patricija van; Buchman, Vladimir L.; Radford, Sheena E.; Brockwell, David J.

doi:10.1038/s41467-022-32687-1

Cited by 27 publications

(48 citation statements)

References 89 publications

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“…Variants of αS with deletions in the N-terminal region were recently created in order to identify regions within the 140 amino acid protein chain that could be important in controlling its amyloid formation propensity. , Doherty et al used in silico analysis to identify two regions in the N-terminal region of αS that exhibit predicted low solubility and high aggregation propensity. These regions include the seven residue sequence 36 GVLYVGS 42 named P1 and the 13 residue sequence 45 KEGVVHGVATVAE 57 named P2.…”

Section: Introductionmentioning

confidence: 99%

“…Deleting P2 alone (ΔP2) had little effect on the half time ( t 50 ) of amyloid formation. However, deleting both P1 and P2 in tandem (ΔΔ) abolished amyloid formation in vitro at both physiological and lysosomal pH within 100 h as shown by ThT fluorescence. , How these deletions control or abolish amyloid formation, however, remained unclear. Deleting these seemingly critical N-terminal sequences may disrupt intramolecular interactions within the protein chain which may affect the ability of αS to achieve an amyloid competent conformation in which the NAC region is sufficiently exposed.…”

Section: Introductionmentioning

confidence: 99%

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Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein

Byrd

Wilkinson

Radford

et al. 2023

J. Am. Soc. Mass Spectrom.

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Αlpha-synuclein (αS) is an intrinsically disordered protein which exhibits a high degree of conformational heterogeneity. In vivo, αS experiences various environments which cause adaptation of its structural ensemble. Divalent metal ions are prominent in synaptic terminals where αS is located and are thought to bind to the αS C-terminal region. Herein, we used native nanoelectrospray ionization ion mobility-mass spectrometry to investigate changes in the charge state distribution and collision cross sections of wild-type N-terminally acetylated (NTA) αS, along with a deletion variant (ΔΔNTA) which inhibits amyloid formation and a C-terminal truncated variant (119NTA) which increases the rate of amyloid formation. We also examine the effect of the addition of divalent metal ions, Ca2+, Mn2+, and Zn2+, and correlate the conformational properties of the αS monomer with the ability to aggregate into amyloid, measured using Thioflavin T fluorescence and negative stain transmission electron microscopy. We find a correlation between the population of species with a low collision cross section and accelerated amyloid assembly kinetics, with the presence of metal ions resulting in protein compaction and causing ΔΔ to regain its ability to form an amyloid. The results portray how the αS conformational ensemble is governed by specific intramolecular interactions that influence its amyloidogenic behavior.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein

Byrd

Wilkinson

Radford

et al. 2023

J. Am. Soc. Mass Spectrom.

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“…On the Alpha-synuclein part the best scoring region was located between positions 32 and 56 (Sup Fig S5). This region was recently shown to be of crucial importance for the aggregation of the protein ( Ulamec et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

PACT - Prediction of Amyloid Cross-interaction by Threading

Wojciechowski

Szczurek

Kotulska

2022

Preprint

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Amyloids are protein aggregates most commonly known for their role in the development of severe neurodegenerative diseases, such as Alzheimer's or Parkinson's disease. However, the unique features of such structures were also beneficially utilized by many organisms for a wide range of physiological roles e.g., biofilm formation and hormone storage. More recent studies have shown that in some cases presence of amyloid aggregates can affect aggregatio kinetics of other proteins. These so-called cross interactions may be crucial for understanding comorbidity of amyloid related diseases, including Alzheimer's disease and type II diabetes. Despite the importance of the process, our understanding of the phenomena is still very limited due to costly and time consuming experiments required to study theinteractions. To overcome this problem, we developed the PACT method. The method is based on modeling of heterogenous fibrils, formed by two amyloidogenic peptides. The resulting structural model is then assessed based on DOPE statistical potential implemented in the Modeller method, based on template based modeling. The main assumption of the method is that pairs of interacting amyloids will be energetically more favorable than negative cases. Importantly, the method can work with long protein fragments and, as a purely physicochemical model, it relies very little on training data. The method, for the first time, opens the possibility of high throughput study of amyloid interactions. The tool is available at: https://github.com/KubaWojciechowski/PACT

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“…That is to say that oligomerization decreases when specific changes in this region are promoted, opening the way for the development of drugs targeting these NAC sub-domains or stabilizing conformations of monomeric -syn where intramolecular interactions shield the NAC region 78,83,84 . In addition, small domains in the NAC flanking regions have also been associated with -syn's aggregation mechanism and function 85,86 , including the domain comprised by amino acids 46-53 where the abovementioned missense mutations, implicated in familial PD, are found. The fact that these mutations are located in the N-term region suggests this segment could be equally important as the NAC domain to the aggregation process.…”

Section: -Synuclein Aggregationmentioning

confidence: 99%

Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

Martins

Galamba

2023

Preprint

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Protein aggregation is implicated in multiple diseases, so-called proteinopathies, ranging from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) to type 2 diabetes mellitus and sickle cell disease (SCD). The structure of the protein aggregates and the kinetics and mechanisms of aggregation have been the object of intense research over the years toward the development of therapeutic routes, including the design of aggregation inhibitors. Nonetheless, the design of drugs targeting aggregation inhibition remains a challenging endeavor because of multiple, disease-specific factors. Herein, we provide a perspective of this therapeutic route with emphasis on small molecules and peptide-based drugs in two diverse diseases, PD and SCD, aiming at establishing links among proposed aggregation inhibitors. The small and large length-scale regimes of the hydrophobic effect are discussed in light of the importance of hydrophobic interactions in proteinopathies. Some simulation results are reported on model peptides, illustrating the impact of hydrophobic and hydrophilic groups in water's hydrogen-bond network with an impact on drug binding. The seeming importance of aromatic rings and hydroxyl groups in protein-aggregation-inhibitor-drugs is emphasized along with the challenges associated with some inhibitors, limiting their development into effective therapeutic options, and questioning the potential of this therapeutic route.

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Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein

Cited by 27 publications

References 89 publications

Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein

Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein

PACT - Prediction of Amyloid Cross-interaction by Threading

Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

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