Influence of the familial Alzheimer's disease–associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide
| Autor: | Tzu-Chun Tang, Stefan N. Constantinescu, Florian Perrin, Jean-Noël Octave, Pascal Kienlen-Campard, Steven O. Smith, Rémi Opsomer, Yi Hu |
|---|---|
| Přispěvatelé: | UCL - SSS/DDUV/SIGN - Cell signalling, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service d'hématologie |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Amyloid-beta (Aβ) Mutant Mutation Missense Peptide Aβ42/Aβ40 ratio Cleavage (embryo) Biochemistry Fluorescence 03 medical and health sciences Protein Domains Alzheimer Disease Extracellular medicine Humans Neurodegeneration Amyloid precursor protein (APP) Nuclear Magnetic Resonance Biomolecular Molecular Biology Fourier transform IR (FTIR) chemistry.chemical_classification Amyloid beta-Peptides 030102 biochemistry & molecular biology biology Molecular Bases of Disease Cell Biology Secretase medicine.disease Peptide Fragments Transmembrane protein Transmembrane domain Membrane interaction 030104 developmental biology Amino Acid Substitution chemistry biology.protein Biophysics Amyloid Precursor Protein Secretases Nuclear magnetic resonance (NMR) Peptides Amyloid precursor protein secretase |
| Zdroj: | The Journal of biological chemistry, Vol. 294, no. 15, p. 5854-5866 (2019) |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.006061 |
| Popis: | Extracellular deposition of β-amyloid (Aβ) peptides in the brain is a hallmark of Alzheimer's disease (AD). Upon β-secretase–mediated cleavage of the β C-terminal fragment (β-CTF) from the Aβ precursor protein, the γ-secretase complex produces the Aβ peptides associated with AD. The familial T43I mutation within the transmembrane domain of the β-CTF (also referred to as C99) increases the ratio between the Aβ42 and Aβ40 peptides largely due to a decrease in Aβ40 formation. Aβ42 is the principal component of amyloid deposits within the brain parenchyma, and an increase in the Aβ42/Aβ40 ratio is correlated with early-onset AD. Using NMR and FTIR spectroscopy, here we addressed how the T43I substitution influences the structure of C55, the minimal sequence containing the entire extracellular and transmembrane (TM) domains of C99 needed for γ-secretase processing. (13)C NMR chemical shifts indicated that the T43I substitution increases helical structure within the TM domain of C55. These structural changes were associated with a shift of the C55 dimer to the monomer and an increase in the tilt of the TM helix relative to the membrane normal in the T43I mutant compared with that of WT C55. The A21G (Flemish) mutation was previously found to increase secreted Aβ40 levels; here, we combined this mutation in the extracellular domain of C99 with T43I and observed that the T43I/A21G double mutant decreases Aβ40 formation. We discuss how the observed structural changes in the T43I mutant may decrease Aβ40 formation and increase the Aβ42/Aβ40 ratio. |
| Databáze: | OpenAIRE |
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