Abeta protofibrils possess a stable core structure resistant to hydrogen exchange
Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer's disease (AD) and other protein aggregation diseases. To better understand the roles...
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American Chemical Society
2009
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ftinfoscience:oai:infoscience.tind.io:142124 2023-06-11T04:09:12+02:00 Abeta protofibrils possess a stable core structure resistant to hydrogen exchange Kheterpal, Indu Lashuel, Hilal A. Hartley, Dean M. Walz, Thomas Lansbury, Peter T. Wetzel, Ronald 2009-10-28T18:31:09Z http://infoscience.epfl.ch/record/142124 https://doi.org/10.1021/bi0357816 https://infoscience.epfl.ch/record/142124/files/bi0357816.pdf unknown American Chemical Society http://infoscience.epfl.ch/record/142124 doi:10.1021/bi0357816 PMID:14640676 https://infoscience.epfl.ch/record/142124/files/bi0357816.pdf http://infoscience.epfl.ch/record/142124 Text 2009 ftinfoscience https://doi.org/10.1021/bi0357816 2023-05-08T00:29:28Z Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer's disease (AD) and other protein aggregation diseases. To better understand the roles of protofibrils in amyloid assembly and Alzheimer's disease, we characterized secondary structural features of these heterogeneous and metastable assembly intermediates. We chromatographically isolated different size populations of protofibrils from amyloid assembly reactions of Abeta(1-40), both wild type and the Arctic variant associated with early onset familial AD, and exposed them to hydrogen-deuterium exchange analysis monitored by mass spectrometry (HX-MS). We show that HX-MS can distinguish among unstructured monomer, protofibrils, and fibrils by their different protection patterns. We find that about 40% of the backbone amide hydrogens of Abeta protofibrils are highly resistant to exchange with deuterium even after 2 days of incubation in aqueous deuterated buffer, implying a very stable, presumably H-bonded, core structure. This is in contrast to mature amyloid fibrils, whose equally stable structure protects about 60% of the backbone amide hydrogens over the same time frame. We also find a surprising degree of specificity in amyloid assembly, in that wild type Abeta is preferentially excluded from both protofibrils and fibrils grown from an equimolar mixture of wild type and Arctic mutant peptides. These and other data are interpreted and discussed in terms of the role of protofibrils in fibril assembly and in disease. Text Arctic EPFL Infoscience (Ecole Polytechnique Fédérale Lausanne) Arctic Biochemistry 42 48 14092 14098 |
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EPFL Infoscience (Ecole Polytechnique Fédérale Lausanne) |
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Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer's disease (AD) and other protein aggregation diseases. To better understand the roles of protofibrils in amyloid assembly and Alzheimer's disease, we characterized secondary structural features of these heterogeneous and metastable assembly intermediates. We chromatographically isolated different size populations of protofibrils from amyloid assembly reactions of Abeta(1-40), both wild type and the Arctic variant associated with early onset familial AD, and exposed them to hydrogen-deuterium exchange analysis monitored by mass spectrometry (HX-MS). We show that HX-MS can distinguish among unstructured monomer, protofibrils, and fibrils by their different protection patterns. We find that about 40% of the backbone amide hydrogens of Abeta protofibrils are highly resistant to exchange with deuterium even after 2 days of incubation in aqueous deuterated buffer, implying a very stable, presumably H-bonded, core structure. This is in contrast to mature amyloid fibrils, whose equally stable structure protects about 60% of the backbone amide hydrogens over the same time frame. We also find a surprising degree of specificity in amyloid assembly, in that wild type Abeta is preferentially excluded from both protofibrils and fibrils grown from an equimolar mixture of wild type and Arctic mutant peptides. These and other data are interpreted and discussed in terms of the role of protofibrils in fibril assembly and in disease. |
format |
Text |
author |
Kheterpal, Indu Lashuel, Hilal A. Hartley, Dean M. Walz, Thomas Lansbury, Peter T. Wetzel, Ronald |
spellingShingle |
Kheterpal, Indu Lashuel, Hilal A. Hartley, Dean M. Walz, Thomas Lansbury, Peter T. Wetzel, Ronald Abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
author_facet |
Kheterpal, Indu Lashuel, Hilal A. Hartley, Dean M. Walz, Thomas Lansbury, Peter T. Wetzel, Ronald |
author_sort |
Kheterpal, Indu |
title |
Abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
title_short |
Abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
title_full |
Abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
title_fullStr |
Abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
title_full_unstemmed |
Abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
title_sort |
abeta protofibrils possess a stable core structure resistant to hydrogen exchange |
publisher |
American Chemical Society |
publishDate |
2009 |
url |
http://infoscience.epfl.ch/record/142124 https://doi.org/10.1021/bi0357816 https://infoscience.epfl.ch/record/142124/files/bi0357816.pdf |
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Arctic |
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Arctic |
genre |
Arctic |
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Arctic |
op_source |
http://infoscience.epfl.ch/record/142124 |
op_relation |
http://infoscience.epfl.ch/record/142124 doi:10.1021/bi0357816 PMID:14640676 https://infoscience.epfl.ch/record/142124/files/bi0357816.pdf |
op_doi |
https://doi.org/10.1021/bi0357816 |
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Biochemistry |
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42 |
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48 |
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14092 |
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14098 |
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1768382969726107648 |