Limits...
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

Normal function of tau protein. Tau protein stabilizes microtubules through four tubulin binding domains (blue boxes) in case of the longest isoform. Binding of tau protein to the microtubules is maintained in equilibrium by coordinated actions of kinases and phosphatases. The phosphorylation of tau (pink balls) regulates its activity to bind to microtubules and can affect axonal transport. Tau protein may inhibit the plus-end-directed transport of vesicles along microtubules by kinesin.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368361&req=5

fig2: Normal function of tau protein. Tau protein stabilizes microtubules through four tubulin binding domains (blue boxes) in case of the longest isoform. Binding of tau protein to the microtubules is maintained in equilibrium by coordinated actions of kinases and phosphatases. The phosphorylation of tau (pink balls) regulates its activity to bind to microtubules and can affect axonal transport. Tau protein may inhibit the plus-end-directed transport of vesicles along microtubules by kinesin.

Mentions: Tau protein binds microtubules through some repeated domains (R1–R4) (encoded by exons 9–12) located at the C-terminus of the molecule (Figure 2) [35]. Each repeat consists of stretches of a highly conserved 18 residues that are imperfectly repeated three times in the fetal tau protein and four times in the adult specific form [35]. The repeats are separated from each other by 13- or 14-residue spacer regions. The main function of tau, aforementioned as a promoter of tubulin polymerization, depends mostly on the MTBR [35, 36]. It has been reported that in vitro tau protein increases the rate of microtubule polymerization and concomitantly inhibits its rate of depolymerization [37]. The 18-amino-acid repeats bind to microtubules through a flexible array of distributed weak sites. The adult form of tau promotes assembly of microtubules more actively than fetal forms [14, 38]. Interestingly, the most potent part that induces microtubule polymerization is the interregion between repeats 1 and 2 (R1-R2 interregion) and more specifically the peptide 275KVQIINKK280 within this sequence [7, 39]. This R1-R2 interregion is unique to 4R tau, adult specific, and responsible for the difference in the binding affinities between 3R and 4R tau [7, 35]. Recent evidence supports a role for the MTBR in the modulation of the phosphorylation state of tau protein. A direct and competitive binding has been demonstrated between this region (residues 224–236 according to the numbering of the longest isoform) and the microtubule on one hand and the same region with the PP2A on the other hand [40]. As a consequence, microtubules could inhibit PP2A activity by competing for binding to tau at the MTBR.


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)

Normal function of tau protein. Tau protein stabilizes microtubules through four tubulin binding domains (blue boxes) in case of the longest isoform. Binding of tau protein to the microtubules is maintained in equilibrium by coordinated actions of kinases and phosphatases. The phosphorylation of tau (pink balls) regulates its activity to bind to microtubules and can affect axonal transport. Tau protein may inhibit the plus-end-directed transport of vesicles along microtubules by kinesin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Normal function of tau protein. Tau protein stabilizes microtubules through four tubulin binding domains (blue boxes) in case of the longest isoform. Binding of tau protein to the microtubules is maintained in equilibrium by coordinated actions of kinases and phosphatases. The phosphorylation of tau (pink balls) regulates its activity to bind to microtubules and can affect axonal transport. Tau protein may inhibit the plus-end-directed transport of vesicles along microtubules by kinesin.
Mentions: Tau protein binds microtubules through some repeated domains (R1–R4) (encoded by exons 9–12) located at the C-terminus of the molecule (Figure 2) [35]. Each repeat consists of stretches of a highly conserved 18 residues that are imperfectly repeated three times in the fetal tau protein and four times in the adult specific form [35]. The repeats are separated from each other by 13- or 14-residue spacer regions. The main function of tau, aforementioned as a promoter of tubulin polymerization, depends mostly on the MTBR [35, 36]. It has been reported that in vitro tau protein increases the rate of microtubule polymerization and concomitantly inhibits its rate of depolymerization [37]. The 18-amino-acid repeats bind to microtubules through a flexible array of distributed weak sites. The adult form of tau promotes assembly of microtubules more actively than fetal forms [14, 38]. Interestingly, the most potent part that induces microtubule polymerization is the interregion between repeats 1 and 2 (R1-R2 interregion) and more specifically the peptide 275KVQIINKK280 within this sequence [7, 39]. This R1-R2 interregion is unique to 4R tau, adult specific, and responsible for the difference in the binding affinities between 3R and 4R tau [7, 35]. Recent evidence supports a role for the MTBR in the modulation of the phosphorylation state of tau protein. A direct and competitive binding has been demonstrated between this region (residues 224–236 according to the numbering of the longest isoform) and the microtubule on one hand and the same region with the PP2A on the other hand [40]. As a consequence, microtubules could inhibit PP2A activity by competing for binding to tau at the MTBR.

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