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A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.

Processing of amyloid precursor protein (APP) by [gamma]-secretase is the last step in the formation of the A[beta] peptides associated Alzheimer's disease. Solid-state NMR spectroscopy is used to establish the structural features of the transmembrane (TM) and juxtamembrane (JM) domains of APP that... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 3, 2009, Vol.106(5), pp.1421-1426
Main Author: Sato, Takeshi
Other Authors: Tang, Tzu-Chun , Reubins, Gabriella , Fei, Jeffrey Z , Fujimoto, Taiki , Kienlen-Campard, Pascal , Constantinescu, Stefan N , Octave, Jean-Noel , Aimoto, Saburo , Smith, Steven O
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0812261106
Link: http://search.proquest.com/docview/66890315/?pq-origsite=primo
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title: A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.
format: Article
creator:
  • Sato, Takeshi
  • Tang, Tzu-Chun
  • Reubins, Gabriella
  • Fei, Jeffrey Z
  • Fujimoto, Taiki
  • Kienlen-Campard, Pascal
  • Constantinescu, Stefan N
  • Octave, Jean-Noel
  • Aimoto, Saburo
  • Smith, Steven O
subjects:
  • Amino Acid Sequence–Chemistry
  • Amyloid Beta-Protein Precursor–Chemistry
  • Animals–Chemistry
  • Cho Cells–Chemistry
  • Cricetinae–Chemistry
  • Cricetulus–Chemistry
  • Cytoplasm–Chemistry
  • Dimerization–Chemistry
  • Hydrolysis–Chemistry
  • Membrane Proteins–Chemistry
  • Models, Molecular–Chemistry
  • Molecular Sequence Data–Chemistry
  • Nuclear Magnetic Resonance, Biomolecular–Chemistry
  • Spectroscopy, Fourier Transform Infrared–Chemistry
  • Amyloid Beta-Protein Precursor
  • Membrane Proteins
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 3, 2009, Vol.106(5), pp.1421-1426
description: Processing of amyloid precursor protein (APP) by [gamma]-secretase is the last step in the formation of the A[beta] peptides associated Alzheimer's disease. Solid-state NMR spectroscopy is used to establish the structural features of the transmembrane (TM) and juxtamembrane (JM) domains of APP that facilitate proteolysis. Using peptides corresponding to the APP TM and JM regions (residues 618-660), we show that the TM domain forms an [alpha]-helical homodimer mediated by consecutive GxxxG motifs. We find that the APP TM helix is disrupted at the intracellular membrane boundary near the [epsilon]-cleavage site. This helix-to-coil transition is required for [gamma]-secretase processing; mutations that extend the TM [alpha]-helix inhibit [epsilon] cleavage, leading to a low production of A[beta] peptides and an accumulation of the [alpha]- and [beta]-C-terminal fragments. Our data support a progressive cleavage mechanism for APP proteolysis that depends on the helix-to-coil transition at the TM-JM boundary and unraveling of the TM [alpha]-helix. Alzheimer's disease | GxxxG motifs | progressive cleavage | solid-state-NMR spectroscopy
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0812261106
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleA helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.
creatorSato, Takeshi ; Tang, Tzu-Chun ; Reubins, Gabriella ; Fei, Jeffrey Z ; Fujimoto, Taiki ; Kienlen-Campard, Pascal ; Constantinescu, Stefan N ; Octave, Jean-Noel ; Aimoto, Saburo ; Smith, Steven O
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ispartofProceedings of the National Academy of Sciences of the United States of America, February 3, 2009, Vol.106(5), pp.1421-1426
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0812261106
subjectAmino Acid Sequence–Chemistry ; Amyloid Beta-Protein Precursor–Chemistry ; Animals–Chemistry ; Cho Cells–Chemistry ; Cricetinae–Chemistry ; Cricetulus–Chemistry ; Cytoplasm–Chemistry ; Dimerization–Chemistry ; Hydrolysis–Chemistry ; Membrane Proteins–Chemistry ; Models, Molecular–Chemistry ; Molecular Sequence Data–Chemistry ; Nuclear Magnetic Resonance, Biomolecular–Chemistry ; Spectroscopy, Fourier Transform Infrared–Chemistry ; Amyloid Beta-Protein Precursor ; Membrane Proteins
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descriptionProcessing of amyloid precursor protein (APP) by [gamma]-secretase is the last step in the formation of the A[beta] peptides associated Alzheimer's disease. Solid-state NMR spectroscopy is used to establish the structural features of the transmembrane (TM) and juxtamembrane (JM) domains of APP that facilitate proteolysis. Using peptides corresponding to the APP TM and JM regions (residues 618-660), we show that the TM domain forms an [alpha]-helical homodimer mediated by consecutive GxxxG motifs. We find that the APP TM helix is disrupted at the intracellular membrane boundary near the [epsilon]-cleavage site. This helix-to-coil transition is required for [gamma]-secretase processing; mutations that extend the TM [alpha]-helix inhibit [epsilon] cleavage, leading to a low production of A[beta] peptides and an accumulation of the [alpha]- and [beta]-C-terminal fragments. Our data support a progressive cleavage mechanism for APP proteolysis that depends on the helix-to-coil transition at the TM-JM boundary and unraveling of the TM [alpha]-helix. Alzheimer's disease | GxxxG motifs | progressive cleavage | solid-state-NMR spectroscopy
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titleA helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.
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titleA helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis.
authorSato, Takeshi ; Tang, Tzu-Chun ; Reubins, Gabriella ; Fei, Jeffrey Z ; Fujimoto, Taiki ; Kienlen-Campard, Pascal ; Constantinescu, Stefan N ; Octave, Jean-Noel ; Aimoto, Saburo ; Smith, Steven O
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