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Ordered and Disordered Segments of Amyloid‐β Drive Sequential Steps of the Toxic Pathway
Author(s) -
Maiti Sudipta,
Maity Barun Kumar,
Das Anand Kant,
Dey Simli,
Moorthi Ullhas Kaarthi,
Kaur Amandeep,
Dey Arpan,
Surendran Dayana,
Pandit Rucha,
Kallianpur Mamata,
Chandra Bappaditya,
Chandrakesan Murlidharan,
Arumugam Senthil
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb203
Subject(s) - biophysics , chemistry , fluorophore , endosome , fluorescence correlation spectroscopy , fluorescence , lipid bilayer , amyloid (mycology) , peptide , intrinsically disordered proteins , microbiology and biotechnology , membrane , intracellular , biology , biochemistry , molecule , inorganic chemistry , physics , organic chemistry , quantum mechanics
While the roles of intrinsically disordered protein domains in driving many interactions are increasingly well‐appreciated, the mechanism of toxicity of disease‐causing disordered proteins remains poorly understood. A prime example is Alzheimer's disease (AD) associated amyloid beta (Aβ). Aβ oligomers are highly toxic partially structured peptide assemblies with a distinct ordered region (residues ~10–40) and a shorter disordered region (residues ~1–9). Here, we investigate the role of this disordered domain and its relation to the ordered domain in the manifestation of toxicity through a set of Aβ fragments and stereo‐isomers designed for this purpose. We have measured their effects on lipid membranes and cultured neurons, probing their toxicity, intracellular distributions, and specific molecular interactions using the techniques of confocal imaging, lattice light sheet imaging, fluorescence lifetime imaging, and fluorescence correlation spectroscopy (FCS). Remarkably, we find that neither part ‐ Aβ 10–40 or Aβ 1–9 , is toxic by itself. The ordered part (Aβ 10–40 ) is the major determinant of how Aβ attaches to lipid bilayers, enters neuronal cells, and localizes primarily in the late endosomal compartments. However, once Aβ enters the cell, it is the disordered part (only when it is connected to the rest of the peptide) which has a strong and stereospecific interaction with an unknown cellular component, as demonstrated by distinct changes in the fluorescence lifetime of a fluorophore attached to the N‐terminal. This interaction appears to commit Aβ to the toxic pathway. Our findings correlate well with Aβ sites of familial AD mutations, a significant fraction of which cluster in the disordered region. We conclude that while the ordered region dictates attachment and cellular entry, the key to toxicity lies in the ordered part presenting the disordered part for a specific cellular interaction. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .