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Structure and pathology of tau protein in Alzheimer disease.

Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D - Int J Alzheimers Dis (2012)

Bottom Line: In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present.The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state.Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Brain Pathophysiology and AD Center, Prague Psychiatric Center, Ústavní 91, 181 03 Prague 8, Czech Republic.

ABSTRACT
Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

No MeSH data available.


Related in: MedlinePlus

Phosphorylation of tau protein. Tau self-assembles mainly through the microtubule binding domains/repeat R3 in 3R tau proteins and through R3 and R2 in 4R tau proteins (R2 (275VQIINK280) and R3 (306VQIVYK311) have β-structure). N-terminal and C-terminal regions to the repeats are inhibitory. Hyperphosphorylation of tau neutralizes these basic inhibitory domains, enabling tau-tau interaction (phosphorylation sites indicated by violet Ps) (modified by [15]).
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fig3: Phosphorylation of tau protein. Tau self-assembles mainly through the microtubule binding domains/repeat R3 in 3R tau proteins and through R3 and R2 in 4R tau proteins (R2 (275VQIINK280) and R3 (306VQIVYK311) have β-structure). N-terminal and C-terminal regions to the repeats are inhibitory. Hyperphosphorylation of tau neutralizes these basic inhibitory domains, enabling tau-tau interaction (phosphorylation sites indicated by violet Ps) (modified by [15]).

Mentions: The molecule of tau has long stretches of positively and negatively charged regions that are not conducive for intermolecular hydrophobic association [81, 110]. The β-structure in monomeric tau is concentrated only in R2 (exon 10) and R3 (exon 11), which can self-assemble by their own into filaments [111] and coassemble with heparin as an artificial inducer [112]. Evidence in vitro has revealed that self-aggregation of tau into filaments is inhibited by the presence of intact N- and C-termini, which lie down over the MTBR and avoid the interaction between these sticky domains [15]. Abnormal phosphorylation of the N-terminal and the C-terminal flanking regions may induce a relaxed structural conformation in the tau molecule that unclip both extremes from the MTBR region. This situation allows the self-interaction between these sticky domains in the formation of PHF/SF (Figure 3) [15].


Structure and pathology of tau protein in Alzheimer disease.

Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D - Int J Alzheimers Dis (2012)

Phosphorylation of tau protein. Tau self-assembles mainly through the microtubule binding domains/repeat R3 in 3R tau proteins and through R3 and R2 in 4R tau proteins (R2 (275VQIINK280) and R3 (306VQIVYK311) have β-structure). N-terminal and C-terminal regions to the repeats are inhibitory. Hyperphosphorylation of tau neutralizes these basic inhibitory domains, enabling tau-tau interaction (phosphorylation sites indicated by violet Ps) (modified by [15]).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368361&req=5

fig3: Phosphorylation of tau protein. Tau self-assembles mainly through the microtubule binding domains/repeat R3 in 3R tau proteins and through R3 and R2 in 4R tau proteins (R2 (275VQIINK280) and R3 (306VQIVYK311) have β-structure). N-terminal and C-terminal regions to the repeats are inhibitory. Hyperphosphorylation of tau neutralizes these basic inhibitory domains, enabling tau-tau interaction (phosphorylation sites indicated by violet Ps) (modified by [15]).
Mentions: The molecule of tau has long stretches of positively and negatively charged regions that are not conducive for intermolecular hydrophobic association [81, 110]. The β-structure in monomeric tau is concentrated only in R2 (exon 10) and R3 (exon 11), which can self-assemble by their own into filaments [111] and coassemble with heparin as an artificial inducer [112]. Evidence in vitro has revealed that self-aggregation of tau into filaments is inhibited by the presence of intact N- and C-termini, which lie down over the MTBR and avoid the interaction between these sticky domains [15]. Abnormal phosphorylation of the N-terminal and the C-terminal flanking regions may induce a relaxed structural conformation in the tau molecule that unclip both extremes from the MTBR region. This situation allows the self-interaction between these sticky domains in the formation of PHF/SF (Figure 3) [15].

Bottom Line: In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present.The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state.Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Brain Pathophysiology and AD Center, Prague Psychiatric Center, Ústavní 91, 181 03 Prague 8, Czech Republic.

ABSTRACT
Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

No MeSH data available.


Related in: MedlinePlus