Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site
The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an in...
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Published in | Nature communications Vol. 5; no. 1; p. 3037 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.01.2014
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Abstract | The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ-secretase for the initial ε-cleavage, and consequently shift cleavage preference towards Aβ42. |
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AbstractList | The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε-cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (kex). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ-secretase for the initial ε-cleavage, and consequently shift cleavage preference towards Aβ42. The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer’s disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of Aβ is generated by γ -secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial ε -cleavage at either T48 or L49, resulting in subsequent production of Aβ42 or Aβ40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen–deuterium exchange rate ( k ex ). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site γ -secretase for the initial ε -cleavage, and consequently shift cleavage preference towards Aβ42. |
ArticleNumber | 3037 |
Author | Xie, Jian Chen, Wen Gamache, Eric Rosenman, David J Li, Yue-Ming Lopez, Maria M Wang, Chunyu |
AuthorAffiliation | 1 Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA 2 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA |
AuthorAffiliation_xml | – name: 1 Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA – name: 2 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA |
Author_xml | – sequence: 1 givenname: Wen surname: Chen fullname: Chen, Wen organization: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA – sequence: 2 givenname: Eric surname: Gamache fullname: Gamache, Eric organization: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA – sequence: 3 givenname: David J surname: Rosenman fullname: Rosenman, David J organization: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA – sequence: 4 givenname: Jian surname: Xie fullname: Xie, Jian organization: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA – sequence: 5 givenname: Maria M surname: Lopez fullname: Lopez, Maria M organization: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA – sequence: 6 givenname: Yue-Ming surname: Li fullname: Li, Yue-Ming organization: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA – sequence: 7 givenname: Chunyu surname: Wang fullname: Wang, Chunyu organization: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24390130$$D View this record in MEDLINE/PubMed |
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Snippet | The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The... The high Aβ42/Aβ40 production ratio is a hallmark of familial Alzheimer’s disease, which can be caused by mutations in the amyloid precursor protein (APP). The... |
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SubjectTerms | Alzheimer Disease Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - chemistry Amyloid beta-Protein Precursor - genetics Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Deuterium Humans Hydrogen Magnetic Resonance Spectroscopy Mutation - genetics Protein Conformation Protein Structure, Tertiary - genetics |
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Title | Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site |
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