Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site
| Autor: | Wen Chen, Eric R. Gamache, Yueming Li, David J. Rosenman, Jian Xie, Chunyu Wang, Maria M. Lopez |
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| Rok vydání: | 2014 |
| Předmět: |
Magnetic Resonance Spectroscopy
Protein Conformation BACE1-AS General Physics and Astronomy Article General Biochemistry Genetics and Molecular Biology Amyloid beta-Protein Precursor Alzheimer Disease mental disorders Amyloid precursor protein Humans APH-1 Genetics Amyloid beta-Peptides Multidisciplinary biology Chemistry P3 peptide General Chemistry Deuterium Protein Structure Tertiary Biochemistry of Alzheimer's disease Transmembrane domain Alpha secretase Biochemistry Mutation biology.protein Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Hydrogen |
| Zdroj: | Nature Communications. 5 |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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