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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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Understanding molecular features of aggregation-resistant tau conformer using oxidized monomer
Benita Jebarupa1, Boby Mathew1, Bindu Y Srinivasu1
1Division of Molecular Medicine, Clinical Proteomics Unit, St. John's Research Institute, St. John's National Academy of Health Sciences, 100 Feet Road, Koramangala, Bangalore 560034, India.
Biochimica Et Biophysica Acta. General Subjects
|March 12, 2019
Summary
Intramolecular disulfide bonds in tau40 prevent aggregation by increasing molecular rigidity, offering a new therapeutic target for Alzheimer's disease (AD) and other tauopathies.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Tau aggregation into paired helical filaments (PHF) is a key feature of Alzheimer's disease (AD).
- Cysteine (Cys)-mediated disulfide bonds influence tau fibrillation, with intermolecular bonds promoting aggregation and intramolecular bonds attenuating it.
- The molecular mechanisms by which intramolecular disulfide bonds resist tau aggregation are not fully understood.
Purpose of the Study:
- To investigate the molecular basis of aggregation-resistant tau conformers.
- To characterize the conformational changes in oxidized tau40 monomers containing intramolecular disulfide bonds.
Main Methods:
- Synthesis of Cys cross-linked tau40 monomer via oxidation.
- Characterization of conformational dynamics using Hydrogen-deuterium exchange, limited proteolysis, and fluorescence quenching.
Main Results:
- Oxidized tau40 exhibited increased rigidity in the microtubule-binding repeat (MTBR) region, including the PHF6 motif, and the C-terminal tail.
- Limited proteolysis confirmed reduced accessibility of the MTBR region in the oxidized tau40 monomer.
- Conformational rigidity and potential intramolecular hydrogen bonding in the MTBR region were observed to inhibit tau assembly.
Conclusions:
- Intramolecular disulfide bonds confer resistance to tau aggregation by inducing conformational changes.
- Stabilizing these aggregation-resistant tau conformers could be a therapeutic strategy for AD and tauopathies.
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