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Increased γ-Site H-Bond Stability Relates to Altered ε-Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP

View ORCID ProfileAlexander Götz, View ORCID ProfilePhilipp Högel, Mara Silber, Iro Chaitoglou, View ORCID ProfileBurkhard Luy, Claudia Muhle-Goll, View ORCID ProfileChristina Scharnagl, View ORCID ProfileDieter Langosch
doi: https://doi.org/10.1101/372698
Alexander Götz
1Lehrstuhl für Physik synthetischer Biosysteme (E14), Technische Universität München, Maximus-von-Imhof Forum 4, 85354 Freising, Germany
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  • ORCID record for Alexander Götz
Philipp Högel
2Center for Integrated Protein Science Munich (CIPSM) at the Lehrstuhl für Chemie der Biopolymere, Technische Universität München, Weihenstephaner Berg 3, 85354 Freising, Germany
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Mara Silber
3Institute of Organic Chemistry and Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Karlsruhe, Germany
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Iro Chaitoglou
2Center for Integrated Protein Science Munich (CIPSM) at the Lehrstuhl für Chemie der Biopolymere, Technische Universität München, Weihenstephaner Berg 3, 85354 Freising, Germany
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Burkhard Luy
3Institute of Organic Chemistry and Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Karlsruhe, Germany
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Claudia Muhle-Goll
3Institute of Organic Chemistry and Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Karlsruhe, Germany
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Christina Scharnagl
1Lehrstuhl für Physik synthetischer Biosysteme (E14), Technische Universität München, Maximus-von-Imhof Forum 4, 85354 Freising, Germany
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  • For correspondence: langosch@tum.de christina.scharnagl@tum.de
Dieter Langosch
2Center for Integrated Protein Science Munich (CIPSM) at the Lehrstuhl für Chemie der Biopolymere, Technische Universität München, Weihenstephaner Berg 3, 85354 Freising, Germany
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  • For correspondence: langosch@tum.de christina.scharnagl@tum.de
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Abstract

Cleavage of the amyloid precursor protein’s (APP) transmembrane domain (TMD) by γ-secretase is a crucial step in the etiology of Alzheimer’s Disease (AD). Mutations in the APP TMD alter cleavage and lead to familial forms of AD (FAD). The majority of FAD mutations shifts the preference of initial cleavage from ε49 to ε48, thus raising the AD-related Aβ42/Aβ40 ratio. The I45T mutation is among the few FAD mutations that do not alter ε-site preference, while it dramatically reduces the efficiency of ε-cleavage. Here we investigate the impact of the I45T mutation on the backbone dynamics of the substrate TMD. Amide exchange experiments and molecular dynamics simulations in solvent and a lipid bilayer reveal an increased stability of amide hydrogen bonds at the ζ-and γ-cleavage sites. Stiffening of the H-bond network is caused by an additional H-bond between the T45 side chain and the TMD backbone, which alters dynamics within the cleavage domain. In particular, the increased H-bond stability inhibits an upward movement of the ε-sites in the I45T mutant. Thus, an altered presentation of ε-sites to the active site of γ-secretase as a consequence of restricted local flexibility provides a rationale for reduced ε-efficiency of the I45T FAD mutant.

  • Abbreviations

    Aβ
    Amyloid β fragment
    AD
    Alzheimer’s disease
    AICD
    Amyloid intracellular domain
    APP
    Amyloid Precursor Protein
    CD
    circular dichroism
    C99
    99 amino acid long fragment of the Amyloid Precursor Protein
    DHX
    deuterium hydrogen exchange
    ETD
    electron transfer dissociation
    ewMCM
    ensemble weighed maximally correlated motion
    FAD
    familial Alzheimer’s disease
    FM
    functional mode
    FMA
    functional mode analysis
    H-bond
    hydrogen bond
    HDX
    hydrogen deuterium exchange
    I45T
    I45T FAD mutation of C99
    LMPG
    lyso-myristoylphosphatidylglycerol
    MD
    molecular dynamics
    MS
    mass-spectrometry
    MSF
    mean-squared fluctuation
    NMR
    Nuclear magnetic resonance spectroscopy
    PLS
    partial least squares
    POPC
    1-palmitoyl-2-oleoylphosphatidylcholine
    TFE
    2,2,2-trifluorethanol
    TM
    transmembrane
    TMD
    transmembrane domain
    TM-C
    C-terminal part of the amyloid precursor protein transmembrane domain
    TM-N
    N-terminal part of the amyloid precursor protein transmembrane domain
    WT
    wild-type
  • Copyright 
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    Posted July 19, 2018.
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    Increased γ-Site H-Bond Stability Relates to Altered ε-Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP
    Alexander Götz, Philipp Högel, Mara Silber, Iro Chaitoglou, Burkhard Luy, Claudia Muhle-Goll, Christina Scharnagl, Dieter Langosch
    bioRxiv 372698; doi: https://doi.org/10.1101/372698
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    Increased γ-Site H-Bond Stability Relates to Altered ε-Efficiency and Aβ Levels in the I45T Familial Alzheimer’s Disease Mutant of APP
    Alexander Götz, Philipp Högel, Mara Silber, Iro Chaitoglou, Burkhard Luy, Claudia Muhle-Goll, Christina Scharnagl, Dieter Langosch
    bioRxiv 372698; doi: https://doi.org/10.1101/372698

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