Abstract
Tau is the major microtubule-associated protein in neuronal axons. It aggregates into "neurofibrillary tangles" during the course of Alzheimer disease. Binding to microtubules and microtubule assembly requires the "repeat domain" in the C-terminal half of Tau, as well as the two regions flanking the repeats. Here we report the NMR characterization of a 198-residue Tau fragment composed of the four tandem repeats and the flanking domains and containing the full microtubule binding and assembly activity of Tau. NMR secondary chemical shifts and dipolar couplings detect the highest propensity for beta-structure within the four-repeat region, whereas the flanking domains are largely random coil, with an increased rigidity in the proline-rich region. Chemical shift perturbation experiments identify two motifs in the upstream flanking domain, (225)KVAVVRT(231) and (243)LQTA(246), and one downstream of the repeats, (370)KIETHKTFREN(380), which strongly contribute to the binding to the acidic outside of microtubules, as well as to the binding of other polyanions such as heparin. This is consistent with the "jaws" model of Tau-microtubule interactions and highlights the importance of the regions flanking the repeats for both microtubule binding and pathological Tau aggregation.
Highlights
Tau, the major MAP2 of neurons, is localized predominantly in axons
Strong MT binding and efficient assembly is achieved when the repeat domain is combined with the flanking domains, whereas the flanking domains alone bind to microtubules but do not promote MT assembly
This leads to the proposition of the “jaws” model of Tau whereby the flanking regions are considered as targeting domains, responsible for positioning Tau on the MT surface, and the repeats are considered as catalytic domains for MT assembly [5, 6]
Summary
The major MAP2 of neurons, is localized predominantly in axons. Tau stabilizes MTs and is necessary for neurite outgrowth [1, 2]. Strong MT binding and efficient assembly is achieved when the repeat domain is combined with the flanking domains, whereas the flanking domains alone bind to microtubules but do not promote MT assembly. This leads to the proposition of the “jaws” model of Tau whereby the flanking regions are considered as targeting domains, responsible for positioning Tau on the MT surface, and the repeats are considered as catalytic domains for MT assembly [5, 6]. To gain a structural understanding of the MT binding and PHF aggregation activities, we performed a detailed NMR characterization of a 198-residue fragment (construct K32), containing the repeat domain and the two flanking domains. The results presented here provide a view of the jaws in Tau that are essential for efficient binding of Tau to microtubules
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