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N-terminal lipid conjugation of amyloid β(1-40) leads to the formation of highly ordered N-terminally extended fibrils.
- Source :
-
Physical chemistry chemical physics : PCCP [Phys Chem Chem Phys] 2017 Jan 18; Vol. 19 (3), pp. 1839-1846. - Publication Year :
- 2017
-
Abstract
- Fibril formation of amyloid β(1-40) (Aβ(1-40)) peptides N-terminally lipid modified with saturated octanoyl or palmitoyl lipid chains was investigated. Lipid modification of Aβ(1-40) significantly accelerates the fibrillation kinetics of the Aβ peptides as revealed by ThT fluorescence. Electron microscopy and X-ray diffraction results indicate a heterogeneous cross-β structure of the fibrils formed by the lipid-conjugated peptides. Solid-state NMR was used to investigate structural features of these fibrils. The lipid moieties form dynamic and loosely structured heterogeneous lipid assemblies as inferred from <superscript>2</superscript> H NMR of the deuterated lipid chains. <superscript>13</superscript> C NMR studies of selected isotopic labels reveals that in addition to Phe <subscript>19</subscript> and Val <subscript>39</subscript> , which are part of the canonical cross-β structure, also N-terminal residues (Ala <subscript>2</subscript> , Phe <subscript>4</subscript> , Val <subscript>12</subscript> ) are found in β-strand conformation. This suggests that the increased hydrophobicity induced by the lipid modification, alters the energy landscape rendering an N-terminal extension of the β-sheet structure favorable. Furthermore, the fibrils formed by the Aβ-lipid hybrids are much more rigid than wildtype Aβ fibrils as inferred from NMR order parameter measurements. Taken together, increasing the local hydrophobicity of the Aβ N-terminus results in highly ordered but heterogeneous amyloid fibrils with extended N-terminal β-sheet structure.
- Subjects :
- Amino Acid Sequence
Hydrophobic and Hydrophilic Interactions
Kinetics
Lipids chemistry
Magnetic Resonance Spectroscopy methods
Micelles
Microscopy, Electron methods
Protein Structure, Secondary
Spectrometry, Fluorescence methods
X-Ray Diffraction methods
Amyloid chemistry
Amyloid beta-Peptides chemistry
Peptide Fragments chemistry
Protein Multimerization
Subjects
Details
- Language :
- English
- ISSN :
- 1463-9084
- Volume :
- 19
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Physical chemistry chemical physics : PCCP
- Publication Type :
- Academic Journal
- Accession number :
- 28000812
- Full Text :
- https://doi.org/10.1039/c6cp05982a