Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides
Some mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβ aggregation. We recently showed that mutations in this region could alter the...
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doaj-170a070f8c3e4f7d9af821f05f808b052020-11-25T02:27:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01212571257110.3390/ijms21072571Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid PeptidesKai-Cyuan He0Yi-Ru Chen1Chu-Ting Liang2Shi-Jie Huang3Chung-Ying Tzeng4Chi-Fon Chang5Shing-Jong Huang6Hsien-Bin Huang7Ta-Hsien Lin8Basic Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei 11217, TaiwanDepartment and Institute of Pharmacology, National Yang-Ming University, Taipei 11221, TaiwanBasic Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei 11217, TaiwanInstitute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei 11221, TaiwanDepartment of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanInstrumentation Center, National Taiwan University, Taipei 10617, TaiwanDepartment of Life Science and the Institute of Molecular Biology, National Chung Cheng University, Chia-yi 62102, TaiwanBasic Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei 11217, TaiwanSome mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβ aggregation. We recently showed that mutations in this region could alter the structural propensity, resulting in a different aggregative propensity of Aβ. Whether these genetic mutations display similar effects remains largely unknown. Here, we characterized the structural propensity and aggregation kinetics of Dutch-type Aβ<sub>40</sub> (Aβ<sub>40</sub>(E22Q)) and its L17A/F19A-substituted mutant (Aβ<sub>40</sub>(L17A/F19A/E22Q)) using circular dichroism spectroscopy, nuclear magnetic spectroscopy, and thioflavin T fluorescence assay. In comparison with wild-type Aβ<sub>40</sub>, we found that Dutch-type mutation, unlike Artic-type mutation (E22G), does not reduce the α-helical propensity of the α/β-discordant region in sodium dodecyl sulfate micellar solution. Moreover, we found that Aβ<sub>40</sub>(L17A/F19A/E22Q) displays a higher α-helical propensity of the α/β-discordant region and a slower aggregation rate than Aβ<sub>40</sub>(E22Q), suggesting that the inhibition of aggregation might be via increasing the α-helical propensity of the α/β-discordant region, similar to that observed in wild-type and Artic-type Aβ<sub>40</sub>. Taken together, Dutch-type and Artic-type mutations adopt different mechanisms to promote Aβ aggregation, however, the L17A/F19A mutation could increase the α-helical propensities of both Dutch-type and Artic-type Aβ<sub>40</sub> and inhibit their aggregation.https://www.mdpi.com/1422-0067/21/7/2571NMRCDAββ-amyloid peptideα/β-discordantDutch-type mutation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kai-Cyuan He Yi-Ru Chen Chu-Ting Liang Shi-Jie Huang Chung-Ying Tzeng Chi-Fon Chang Shing-Jong Huang Hsien-Bin Huang Ta-Hsien Lin |
spellingShingle |
Kai-Cyuan He Yi-Ru Chen Chu-Ting Liang Shi-Jie Huang Chung-Ying Tzeng Chi-Fon Chang Shing-Jong Huang Hsien-Bin Huang Ta-Hsien Lin Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides International Journal of Molecular Sciences NMR CD Aβ β-amyloid peptide α/β-discordant Dutch-type mutation |
author_facet |
Kai-Cyuan He Yi-Ru Chen Chu-Ting Liang Shi-Jie Huang Chung-Ying Tzeng Chi-Fon Chang Shing-Jong Huang Hsien-Bin Huang Ta-Hsien Lin |
author_sort |
Kai-Cyuan He |
title |
Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides |
title_short |
Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides |
title_full |
Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides |
title_fullStr |
Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides |
title_full_unstemmed |
Conformational Characterization of Native and L17A/F19A-Substituted Dutch-Type β-Amyloid Peptides |
title_sort |
conformational characterization of native and l17a/f19a-substituted dutch-type β-amyloid peptides |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-04-01 |
description |
Some mutations which occur in the α/β-discordant region (resides 15 to 23) of β-amyloid peptide (Aβ) lead to familial Alzheimer’s disease (FAD). In vitro studies have shown that these genetic mutations could accelerate Aβ aggregation. We recently showed that mutations in this region could alter the structural propensity, resulting in a different aggregative propensity of Aβ. Whether these genetic mutations display similar effects remains largely unknown. Here, we characterized the structural propensity and aggregation kinetics of Dutch-type Aβ<sub>40</sub> (Aβ<sub>40</sub>(E22Q)) and its L17A/F19A-substituted mutant (Aβ<sub>40</sub>(L17A/F19A/E22Q)) using circular dichroism spectroscopy, nuclear magnetic spectroscopy, and thioflavin T fluorescence assay. In comparison with wild-type Aβ<sub>40</sub>, we found that Dutch-type mutation, unlike Artic-type mutation (E22G), does not reduce the α-helical propensity of the α/β-discordant region in sodium dodecyl sulfate micellar solution. Moreover, we found that Aβ<sub>40</sub>(L17A/F19A/E22Q) displays a higher α-helical propensity of the α/β-discordant region and a slower aggregation rate than Aβ<sub>40</sub>(E22Q), suggesting that the inhibition of aggregation might be via increasing the α-helical propensity of the α/β-discordant region, similar to that observed in wild-type and Artic-type Aβ<sub>40</sub>. Taken together, Dutch-type and Artic-type mutations adopt different mechanisms to promote Aβ aggregation, however, the L17A/F19A mutation could increase the α-helical propensities of both Dutch-type and Artic-type Aβ<sub>40</sub> and inhibit their aggregation. |
topic |
NMR CD Aβ β-amyloid peptide α/β-discordant Dutch-type mutation |
url |
https://www.mdpi.com/1422-0067/21/7/2571 |
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