On the role of sidechain size and charge in the aggregation of A
            <i>β</i>
            42 with familial mutations

Yang, Xiaoting; Meisl, Georg; Frohm, Birgitta; Thulin, Eva; Knowles, Tuomas P. J.; Linse, Sara

doi:10.1073/pnas.1803539115

Cited by 108 publications

(140 citation statements)

References 38 publications

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“…Overall, the in silico study indicates that the E22K mutation alters 3Aβ 11−40 to be larger, more stable and have stronger interaction with DPPC membrane lipid bilayer. The results are in good agreement with experiments that E22K amyloid faster self-aggregates [44].…”

Section: Discussionsupporting

confidence: 91%

“…progress. The lacking of the α-content may imply that the E22K mutation probably enhances the folding rate of Aβ peptides [44,45]. The per-residue structure terms were also determined as displayed in Fig.…”

Section: Iii2 Secondary Structure Of the Mutationmentioning

confidence: 99%

“…The amount is significantly larger than that of tmWT trimer with the value of 10.5 ± 1.6. Because the stronger contacts probably enhance the Aβ self-aggregate [48], it may be argued that the formation rate of the trimer is probably boosted when the mutation is induced [44,49].…”

Section: Iii4 Contacts Of Aβ Chain With Other Chains and Dppc Lipidmentioning

confidence: 99%

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Computational Investigations of the Transmembrane Italian-Mutant (E22K) 3A\(\beta_{11 - 40}\) in Aqueous Solution

Ngo¹

2018

Comm. in Phys.

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The Amyloid beta A(β ) oligomers are characterized as critical cytotoxic materials in Alzheimer's disease (AD) pathogenesis. Structural details of transmembrane oligomers are inevitably necessary to design/search potential inhibitor to treat AD. However, the experimental detections for structural information of low-order Aβ oligomers are precluded due to the extremely dynamic fluctuation of the oligomers. In this project, the transmembrane Italian-mutant (E22K) 3Aβ 11−40 (tmE22K 3Aβ 11−40 ) was extensively investigated using the temperature replica exchange molecular dynamics (REMD) simulations. The structural changes of the trimer when replacing the negatively charged residue E22 by a positively charged residue K were monitored over simulation intervals. The oligomer size turned to be larger and the increase of β -content was recorded. The momentous gain of intermolecular contacts with lipid molecules implies that tmE22K 3Aβ 11−40 would be self-inserted more easily into the membrane than the wild-type (WT) form. Furthermore, the tighter interaction between constituting monomers was indicated implying that the E22K mutation probably enhances the Aβ fibril formation. The results are in good agreement with experiments showing that E22K amyloid self-aggregates faster than the WT form. Detailed information of tmE22K trimer structure and kinetics probably yield the understanding of AD mechanism.

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Section: Discussionsupporting

confidence: 91%

Section: Iii2 Secondary Structure Of the Mutationmentioning

confidence: 99%

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Computational Investigations of the Transmembrane Italian-Mutant (E22K) 3A\(\beta_{11 - 40}\) in Aqueous Solution

Ngo¹

2018

Comm. in Phys.

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“…4A,B). The multi-step model additionally includes saturation of secondary nucleation and was previously shown to be applicable for the shorter Aβ 40 and Aβ M40 variants 13,29,42 and for Aβ M42 at pH 7.4 43 , which all exhibit higher γ-values, but also describes well the kinetics of Aβ M42 at pH 8.0 44 . Hence, these results confirm that the native and isotope-labeled peptides obtained herein are highly pure and in a monomeric state, which is essential for accurate and reproducible aggregation kinetics experiments.…”

Section: Production Of 4-fluoro-phe-labeled Aβ Peptides the Present mentioning

confidence: 99%

High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain

Abelein

Chen

Aleksis

et al. 2020

Sci Rep

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During storage in the silk gland, the n-terminal domain (nt) of spider silk proteins (spidroins) keeps the aggregation-prone repetitive region in solution at extreme concentrations. We observe that nts from different spidroins have co-evolved with their respective repeat region, and now use an NT that is distantly related to previously used NTs, for efficient recombinant production of the amyloid-β peptide (Aβ) implicated in Alzheimer's disease. A designed variant of nt from Nephila clavipes flagelliform spidroin, which in nature allows production and storage of β-hairpin repeat segments, gives exceptionally high yields of different human Aβ variants as a solubility tag. This tool enables efficient production of target peptides also in minimal medium and gives up to 10 times more isotope-labeled monomeric Aβ peptides per liter bacterial culture than previously reported.Orb-weaving spiders manufacture up to seven different silks, e.g. dragline silk derived from major ampullate silk proteins (spidroins, MaSp) and flagelliform silk derived from flagelliform spidroins (FlSp). The various spidroins share a common architecture -a large core repetitive region capped by globular N-and C-terminal domains (NT and CT) 1 . The divergent and large aggregation-prone repetitive regions of the spidroins determine the mechanical properties of the respective spider silks, while the terminal domains regulate silk fiber formation 2,3 . Despite their high aggregation propensity the spidroins can be stored at extremely high concentrations (30-50% w/v) in the spider silk gland, solubilized by the NT domain 1,4 .The NT dimerizes upon a drop in pH, which is crucial for silk fiber formation 1,5 . To ensure solubility also at low pH and widen the applicability of NT as a solubility enhancing fusion partner, a charged-reversed mutant has been designed (referred to as NT* MaSp ) 6 . The previously reported NT* MaSp tag is derived from the NT domain of Euprosthenops australis MaSp1 and folds as a five-helix bundle 6,7 . NT* MaSp is a pH insensitive constitutive monomer, highly stable and extremely soluble, and has been successfully applied for efficient production and purification of, among others, lung surfactant protein analogs, cholecystokinin-58, human antimicrobial cathelicidin and a designed β-sheet protein 6,8 .Aggregation-prone proteins and peptides are associated with several neurodegenerative disorders, e.g. Alzheimer's disease (AD), the most prevalent form of dementia 9,10 . These proteins/peptides often exhibit high β-sheet propensity, which make them prone to aggregate and form insoluble amyloid fibrils 11 . These intrinsic properties of amyloid-forming proteins make high-yield biochemical production challenging, yet the availability of pure protein samples is crucial for studying protein self-assembly and its associated neurotoxicity in vitro and in vivo. This is probably one important reason behind the fact that, despite immense efforts, the exact mechanisms of Aβ self-assembly are still unknown 9-11 . Recent advances have howe...

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“…Consequently, the self-aggregation rate of D23N oligomers has been shown to increase. 30 Therefore, studying the impact of the D23N mutation on the self-assembly has been carried out for a number of Ab peptide systems, including Ab 21-30 , 31 Ab 10-35 , 32 Ab 1-40 , 33 Ab 1-42 , 34 2Ab 1-40 , 35 and 6Ab [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] . 36 However, the effect of D23N mutation on Ab 40 trimer (3Ab 40 ), one of the most neurotoxic Ab oligomers, 10,11 has not been revealed.…”

Section: Introductionmentioning

confidence: 99%

Atomistic investigation of an Iowa Amyloid-β trimer in aqueous solution

Ngo

Phung

et al. 2018

RSC Adv.

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On the role of sidechain size and charge in the aggregation of A β 42 with familial mutations

Cited by 108 publications

References 38 publications

Computational Investigations of the Transmembrane Italian-Mutant (E22K) 3A\(\beta_{11 - 40}\) in Aqueous Solution

Computational Investigations of the Transmembrane Italian-Mutant (E22K) 3A\(\beta_{11 - 40}\) in Aqueous Solution

High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain

Atomistic investigation of an Iowa Amyloid-β trimer in aqueous solution

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