Tau protein kinases: Involvement in Alzheimer's disease

Martin, Ludovic; Latypova, Xénia; Wilson, Cornelia M.; Magnaudeix, Amandine; Perrin, Marie-Laure; Yardin, Catherine; Terro, Faraj

doi:10.1016/j.arr.2012.06.003

Cited by 533 publications

(446 citation statements)

References 312 publications

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“…domain -Fyn is an important kinase containing an SH3 domain and phosphorylationg single tyrosine residues in different regions of the compared proteins: Tyr 18 in Tau (12) and Tyr 67 in MAP2c (53). In general, SH3 domains bind to proteins with the sequential motif PXXP, preferably with positively charged amino acids in its vicinity.…”

Section: Site Of Interaction With Canonical Fyn Sh3mentioning

confidence: 99%

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Functionally specific binding regions of microtubule-associated protein 2c exhibit distinct conformations and dynamics

Melková

Zapletal

Jansen

et al. 2018

Journal of Biological Chemistry

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Microtubule-associated protein 2c (MAP2c)1 is a 49-kDa intrinsically disordered protein regulating the dynamics of microtubules in developing neurons. MAP2c differs from its sequence homologue Tau in the pattern and kinetics of phosphorylation by cAMP-dependent protein kinase (PKA). Moreover, the mechanisms through which MAP2c interacts with its binding partners and the conformational changes and dynamics associated with these interactions remain unclear. Here, we used NMR relaxation and paramagnetic relaxation enhancement techniques to determine the dynamics and longrange interactions within MAP2c. The relaxation rates revealed large differences in flexibility of individual regions of MAP2c, with the lowest flexibility observed in the known and proposed binding sites. Quantitative conformational analyses of chemical shifts, small angle X-ray scattering (SAXS), and paramagnetic relaxation enhancement measurements disclosed that MAP2c regions interacting with important protein partners, including Fyn tyrosine kinase, plectin, and PKA, adopt specific conformations. High populations of poly-proline II and α-helices were found in Fyn-and plectin-binding sites of MAP2c, respectively. The region binding regulatory subunit of PKA consists of two helical motifs bridged by a more extended conformation. Of note, although MAP2c and Tau did not differ substantially in their conformations in regions of high sequence identity, we found that they differ significantly in long-range interactions, dynamics, and local conformation motifs in their N-terminal domains. These results highlight that the N-terminal regions of MAP2c provide important specificity to its regulatory roles and indicate a close relationship between MAP2c's biological functions and conformational behavior.Cytoskeletal microtubule associated proteins (MAPs) bind, stabilize, and regulate dynam- Conformation and Dynamics of MAP2cics of microtubules, in a phosphorylation-dependant manner. MAP2 and Tau are neuronal MAPs, MAP2 being expressed mainly in dendrites, whereas Tau is found in axons (1). Both MAP2 and Tau are expressed as different spliced variants. Tau isoforms expressed in human brain differ in the number of near-amino terminal inserts as well as in the number of repeats in the Microtubule Binding Domain (MTBD), whereas MAP2 isoforms differ in the length of the N-terminal projection domain (2, 3). Expression of both MAP2 and Tau isoforms is regulated during development. The high-molecular weight isoforms, MAP2a and MAP2b, contain 1830 amino-acids, and the two low molecular weight variants, MAP2c and MAP2d, consist of 467 and 498 amino acids, respectively. MAP2c is the smallest functional isoform, expressed mainly during embryonal brain development. After birth, its expression is restricted to regions exhibiting post-natal plasticity, such as the olfactory bulb (4), suggesting a role in neuronal development.Tau and MAP2c share a high sequence homology in the C-terminal part, containing MTBD, but differ in the N-terminal part, comprising the acidi...

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Section: Site Of Interaction With Canonical Fyn Sh3mentioning

confidence: 99%

“…1) (5). The sequence diversity is further magnified by different phosphorylation patterns (6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Functionally specific binding regions of microtubule-associated protein 2c exhibit distinct conformations and dynamics

Melková

Zapletal

Jansen

et al. 2018

Journal of Biological Chemistry

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“…The longest Tau protein isoform (441 residues) has 80 threonine (Thr) or serine (Ser) residues. These residues are exposed as Tau is an intrinsically disordered protein subject to modification by numerous kinases (7). Mass spectrometry (MS) analyses have identified ϳ45 phosphorylated sites on Tau aggregates extracted from AD patients with a typical paired helical filament (PHF) morphology (8,9) compared with 15-30 phosphorylation sites in soluble Tau extracted from mice (10) or normal human brain (11).…”

mentioning

confidence: 99%

Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase

Prabakaran

Cantrelle

et al. 2016

Journal of Biological Chemistry

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Tau neuronal protein has a central role in neurodegeneration and is implicated in Alzheimer disease development. Abnormal phosphorylation of Tau impairs its interaction with other proteins and is associated with its dysregulation in pathological conditions. Molecular mechanisms leading to hyperphosphorylation of Tau in pathological conditions are unknown. Here, we characterize phosphorylation of Tau by extracellular-regulated kinase (ERK2), a mitogen-activated kinase (MAPK) that responds to extracellular signals. Analysis of in vitro phosphorylated Tau by activated recombinant ERK2 with nuclear magnetic resonance spectroscopy (NMR) reveals phosphorylation of 15 Ser/Thr sites. In vitro phosphorylation of Tau using rat brain extract and subsequent NMR analysis identifies the same sites. Phosphorylation with rat brain extract is known to transform Tau into an Alzheimer disease-like state. Our results indicate that phosphorylation of Tau by ERK2 alone is sufficient to produce the same characteristics. We further investigate the mechanism of ERK2 phosphorylation of Tau. Kinases are known to recognize their protein substrates not only by their specificity for a targeted Ser or Thr phosphorylation site but also by binding to linear-peptide motifs called docking sites. We identify two main ERK2 docking sites in Tau sequence using NMR. Our results suggest that ERK2 dysregulation in Alzheimer disease could lead to abnormal phosphorylation of Tau resulting in the pathology of the disease.Tau is an intrinsically disordered protein whose primary sequence is divided into several functional domains: an N-terminal region, a proline-rich domain (PRD), 2 a microtubule binding domain (MTBD) constituted of partially repeated sequences R1 to R4, and a C-terminal region (see Fig. 1A). Both PRD and MTBD are involved in microtubule stabilizing activity of Tau (1, 2).Phosphorylation of Tau is an essential process to regulate its physiological function(s); however, abnormal phosphorylation of Tau has been linked to neuronal dysfunction (3-5). In Alzheimer disease (AD) Tau is hyperphosphorylated and aggregated (6). The longest Tau protein isoform (441 residues) has 80 threonine (Thr) or serine (Ser) residues. These residues are exposed as Tau is an intrinsically disordered protein subject to modification by numerous kinases (7). Mass spectrometry (MS) analyses have identified ϳ45 phosphorylated sites on Tau aggregates extracted from AD patients with a typical paired helical filament (PHF) morphology (8, 9) ERK2 belongs to the mitogen-activated protein kinase (MAPKs) family and is activated by dual phosphorylation on a Thr-Xaa-Tyr sequence in its activation loop by MAP kinase kinases (MKK) (21-23). Human ERK2 is phosphorylated on Thr-183 and Tyr-185 by MEK kinase. MAP kinases have a classic kinase structure with an N-terminal lobe folded as a ␤ sheet associated to a larger C-terminal domain constituted of ␣-helices (24). The activation loop is located at the hinge between these domains and shows a large conformational change upon phosphor...

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“…Several cellular factors have been reported to affect tau aggregation, such as post-translational modifications including phosphorylation and acetylation (see review for further information [54,55]), and proteolysis, including the molecular chaperone machinery. Tau proteolytic cleavage could play an important role in tau aggregation.…”

Section: Tau Truncationmentioning

confidence: 99%