title: Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site.
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.
authors.affiliation: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Gamache
authors.affiliation: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rosenman
authors.affiliation: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Lopez
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th Street, Troy, New York 12180, USA.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics*; D003903:Deuterium; D006801:Humans; D006859:Hydrogen; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006859:Hydrogen; D003903:Deuterium; D053829:Amyloid Precursor Protein Secretases