The effect of a DeltaK280 mutation on the unfolded state of a microtubule-binding repeat in Tau.
Abstract
Tau is a natively unfolded protein that forms intracellular aggregates in the brains of patients with Alzheimer's disease. To decipher the mechanism underlying the formation of tau aggregates, we developed a novel approach for constructing models of natively unfolded proteins. The method, energy-minima mapping and weighting (EMW), samples local energy minima of subsequences within a natively unfolded protein and then constructs ensembles from these energetically favorable conformations that are consistent with a given set of experimental data. A unique feature of the method is that it does not strive to generate a single ensemble that represents the unfolded state. Instead we construct a number of candidate ensembles, each of which agrees with a given set of experimental constraints, and focus our analysis on local structural features that are present in all of the independently generated ensembles. Using EMW we generated ensembles that are consistent with chemical shift measurements obtained on tau constructs. Thirty models were constructed for the second microtubule binding repeat (MTBR2) in wild-type (WT) tau and a DeltaK280 mutant, which is found in some forms of frontotemporal dementia. By focusing on structural features t...Continue Reading
References
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Protein backbone angle restraints from searching a database for chemical shift and sequence homology
Conformational sampling with implicit solvent models: application to the PHF6 peptide in tau protein
Citations
Intrinsically disordered proteins: from sequence and conformational properties toward drug discovery
Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases
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Software Mentioned
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