The effect of a DeltaK280 mutation on the unfolded state of a microtubule-binding repeat in Tau.
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 that are preserved across all ensembles, we find that the aggregation-initiating sequence, PHF6*, prefers an extended conformation in both the WT and DeltaK280 sequences. In addition, we find that residue K280 can adopt a loop/turn conformation in WT MTBR2 and that deletion of this residue, which can adopt nonextended states, leads to an increase in locally extended conformations near the C-terminus of PHF6*. As an increased preference for extended states near the C-terminus of PHF6* may facilitate the propagation of beta-structure downstream from PHF6*, these results explain how a deletion at position 280 can promote the formation of tau aggregates.
Huang
Austin
A
Department of Electrical Engineering and Computer Science, Harvard-MIT Division of Health Sciences and Technology, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Stultz
Collin M
CM
D020816:Amino Acid Motifs; D019281:Dimerization; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D020449:Repetitive Sequences, Amino Acid / Q000502:physiology; D018511:Systems Integration; D013816:Thermodynamics; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure
D016875:tau Proteins; D008239:Lysine