Phosphorylated tau can promote tubulin assembly (original) (raw)
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The FASEB Journal, 2008
In Alzheimer disease (AD)-affected neurons, the Tau protein is found in an aggregated and hyperphosphorylated state. A common hypothesis is that Tau hyperphosphorylation causes its dissociation from the microtubular surface, with consequently a breakdown of the microtubules (MTs) and aggregation of the unbound Tau. We evaluated the effect of Tau phosphorylation on both tubulin assembly and MT binding. We show that the cyclin-dependent kinase 2/cyclin A3 kinase complex can generate the AT8 and AT180 AD-specific phospho-epitopes and use NMR spectroscopy to validate qualitatively and quantitatively the phospho content of our samples. The simultaneous presence of both epitopes disables the tubulin assembly capacity of Tau in conditions whereby Tau is the driving force for the assembly process but does not, however, inhibit MT assembly when the latter is driven by an increased tubulin concentration. When compared to the isolated MT binding repeats (K d 3.0؍ M), the phospho-Tau retains a substantial affinity for preformed MTs (K d 11؍ nM), suggesting that the phosphorylated proline-rich region still participates in the binding event. Our results hence indicate that the sole phosphorylation at the AT8/AT180 epitopes, although leading to a functional defect for Tau, is not sufficient for its dissociation from the MT surface and subsequent aggregation as observed in AD.
European Journal of Neuroscience, 2007
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline-rich (residues 172-251) and C-terminal tail (residues 368-441) regions, which flank the microtubule-binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its selfaggregation. We found that tau phosphorylation at the proline-rich region by dual-specificity tyrosine-phosphorylated and -regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self-aggregation slightly. Tau phosphorylation at the C-terminal tail region by glycogen synthase kinase-3β increased its activity and promoted its self-aggregation markedly. Tau phosphorylation at both regions plus the microtubule-binding region by cAMPdependent protein kinase diminished its activity (~70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self-aggregation by phosphorylation at various sites/regions.
Avicenna Journal of Medical Biotechnology, 2020
Background: Tau is a disordered Microtubule Associated Protein (MAP) which prefers to bind and stabilize microtubules. Phosphorylation of tau in particular enhances tau-tubulin interaction which otherwise detaches from tubulin during hyperphosphorylation. The reason behind their destabilization, detachment and the role of β subunit (from microtubule) and the projection domain (Tau) in microtubule stability remains elusive till date. Thus, a complete 3D structural investigation of tau protein is much needed to address these queries as the existing crystal structures are in fragments and quite limited. Methods: In this study, the modelled human tau protein was subjected to phosphorylation and hyperphosphorylation which were later considered for docking with microtubules (βα subunits-inter dimer) and vinblastine. Results: Phosphorylated tau protein interacts with both α- and β subunits. But stronger bonding was with α- compared to β subunits. Regarding β subunit, proline rich loop and ...
Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects
Frontiers in Aging Neuroscience
Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural and functional elements in axons, supporting neurite differentiation and growth, as well as transporting motor proteins along the axons, which use MTs as support tracks. Tau is a stabilizing MT associated protein, whose functions are mainly regulated by phosphorylation. A disruption of the MT network, which might be caused by Tau loss of function, is observed in a group of related diseases called tauopathies, which includes Alzheimer's disease (AD). Tau is found hyperphosphorylated in AD, which might account for its loss of MT stabilizing capacity. Since destabilization of MTs after dissociation of Tau could contribute to toxicity in neurodegenerative diseases, a molecular understanding of this interaction and its regulation is essential.
FEBS Letters, 1996
The abnormal cytoskeletal organization observed in Alzheimer's disease has been suggested to arise from hyperpbosphorylation of tau and the resultant elimination of its ability to associate with microtubules. This possibility has been supported by a number of studies under cell-free conditions utilizing various kinases, phosphatases and their corresponding inhibitors each, and by treatment of intact cells with kinase and phosphatase activators and inhibitors. However, in studies utilizing intact cells, it remained difficult to attribute mierotubule compromise specifically to tau hyperphosphorylation due to potential influence of inhibitors on tubuliu and/or other microtubule-associated proteins, which themselves possess assembly-regulatory phosphorylation sites. To address this difficulty, we subjected SH-SY-SY human neuroblastoma cells to treatment with the phosphatase inhibitor okadaic acid (OA), which has been previously demonstrated to depolymerize microtubules in these cells. OA induced an increase in tau hyperphosphorylation as evidenced by an increase in Alz-50 immunoreactivity and a corresponding decrease in Tau-1 immunoreactivity. When tau-enriched fractions from OA-treated cells were incubated under microtubule assemblypromoting conditions with twice-cycled, tau-free preparations of bovine brain tubulin not exposed to OA, Alz-50-immuuoreactive tau isoforms displayed a marked (49%) reduction in ability to co-assemble with bovine micrutubules as compared with Tau-1and 5E2-immunoreactive isoforms. These data indicate that hyperphosphorylated tau has a reduced capacity to associate with microtubules, and support the hypothesis that tau hyperphosphorylation may underlie microtubule breakdown in Alzbeimer's disease.
Tau Induces Ring and Microtubule Formation from αβ-Tubulin Dimers under Nonassembly Conditions †
Biochemistry, 2004
Tau is a neuronal microtubule-associated protein that plays a central role in many cellular processes, both physiological and pathological, such as axons stabilization and Alzheimer's disease. Despite extensive studies, very little is known about the detailed molecular basis of tau binding to microtubules. We used the four-repeat recombinant htau40 and tubulin dimers to show for the first time that tau is able to induce both microtubule and ring formation from 6S R tubulin in phosphate buffer without added magnesium (nonassembly conditions). The amount of microtubules or rings formed was protein concentration-, temperature-, and nucleotide-dependent. By means of biophysical approaches, we showed that tau binds to tubulin without global-folding change, detectable by circular dichroism. We also demonstrated that the tau-tubulin interaction follows a ligand-mediated elongation process, with two tau-binding site per tubulin dimer. Moreover, using a tubulin recombinant R-tubulin C-terminal fragment (404-451) and a -tubulin C-terminal fragment (394-445), we demonstrated the involvement of both of these tubulin regions in tau binding. From this model system, we gain new insight into the mechanisms by which tau binds to tubulin and induces microtubule formation.
Current Medicinal Chemistry, 2008
Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.
The Journal of biological chemistry, 1994
The neuronal microtubule-associated protein tau promotes microtubule assembly and has been implicated in the development of axonal morphology. To study the effect of phosphorylation and substrate modulation on tau's distinct activities to promote growth of existing microtubules and nucleation of new ones, we phosphorylated bacterially expressed human tau by cAMP-dependent protein kinase in the absence or presence of heparin, an acidic substrate modulator. We found that heparin increased phosphorylation of tau by a factor of more than 2 and produced tau bands with decreased electrophoretic mobility. We demonstrate that phosphorylation of tau in the absence or presence of heparin similarly reduced tau's activity to promote microtubule growth, whereas tau's activity to promote microtubules was suppressed much more after phosphorylation in the presence of heparin. Using recombinant tau fragments we showed that heparin-induced phosphorylation caused a specific shift in electr...
Microtubule depolymerization and tau phosphorylation
Journal of Alzheimer's disease : JAD, 2013
Inge Grundke-Iqbal and Khalid Iqbal found a connection between microtubule associated tau and Alzheimer's disease. They described that abnormally phosphorylated tau is a component of the paired helical filaments found in the disease. Afterwards they described that tau hyperphosphorylation prevents microtubule assembly. Now trying to complement the relationship between microtubules and tau phosphorylation, we have commented on the effect of microtubule disassembly on tau phosphorylation. In this study, we investigated the role of microtubule depolymerization induced by nocodazole on tau phosphorylation in human neuroblastoma SH-SY5Y cells. Our results indicate that nocodazole provokes tau phosphorylation mediated by GSK3, as determined by using AT-8 or Tau-1 antibodies. Interestingly, total GSK3β and GSK3β phosphorylation on Ser-9 are not altered during nocodazole treatment. In addition, microtubule stabilization with taxol had similar effects, likely because taxol and tau compet...