|Home||The Tau Protein|
Tau is one of several types of microtubule-associated proteins (MAPs), responsible for the assembly and stability of microtubule networks. Although microtubule networks exist in all kinds of animal and plant cells, Tau is present only in neurons and predominantly localized in axons.
Tau is a major component of neurofibrillary tangles. Recently, it has received greater attention because more and more evidence has indicated that hyperphosphorylation of Tau is the origin of Alzheimer's disease (AD). Phosphorylation is a process that adds a phosphate group to a protein, particularly on the amino acid serine, threonine or tyrosine. In an AD brain, too many residues in the Tau protein are phosphorylated.
Amino Acid Sequence
Tau has six isoforms produced from a single gene through alternative RNA splicing. The longest isoform has 441 amino acid residues and the shortest one has 352 residues. In the longest isoform, there are 56 negative residues (D or E), most of them are located in the first 150 residues.
Figure 5-2. The functional domains of the Tau protein.
The six isoforms differ in the number of repeats at the C-terminal half and the number of inserts at the N-terminal half. The number of repeats may be either 3 or 4 and the number of inserts may be 0,1 or 2.
Tau binds to the microtubule through the repeats and their flanking regions (Preuss et al., 1997). Upon binding, the N-terminal portion (< 150 residues) protrudes from the microtubule surface. For this reason, the N-terminal portion is called projection domain, which may bind to other cell components such as the plasma membrane.
In the middle of the Tau protein, there is a proline-rich region which contains several PXXP motifs. This motif is known to interact with proteins containing Src homology 3 domains (SH3). An important example is Fyn, which is a tyrosine kinase - the enzyme that catalyzes phosphorylation on tyrosine. Fyn works with Tau during the production of myelin sheath - a layer wrapping around the axon (Klein et al., 2002). Experiments have demonstrated that, without Fyn, beta amyloid cannot induce neurotoxicity (Roberson et al., 2011).
The longest isoform of Tau contains more than 60 potential phosphorylation sites. Among them, five are tyrosine residues, which exist in all isoforms. They are located at 18, 29, 197, 310 and 394 (numbering is based on the longest isoform). The tyrosine kinase Fyn preferentially targets tyosine-18 (Y18), which is phosphorylated in the AD brain and at early developmental stages in mice, but not in healthy adult. Phosphorylation of Y18 does not significantly alter the microtubule binding (Lee et al., 2004), consistent with its location at the projection domain which may bind to other components such as the plasma membrane.
Another tyrosine residue, Y394, is also phosphorylated in both AD brain and fetal brain. The phosphorylation has little effect on microtubule binding. Unlike Y18, Y394 is targeted by tyrosine kinase c-Abl (Derkinderen et al., 2005). The finding that these residues are phosphorylated in fetus indicates that their phosphorylation has normal functions during development. In fact, it has been known for many years that Tau is highly phosphorylated in the fetal brain, but minimally phosphorylated in the healthy adult brain (Augustinack et al., 2002).
In the tangles, many serine and threonine residues are phosphorylated (Hanger et al., 1998). Among them, S262, S293, S324, and S356 are in the repeats; S199, S202, T205, T212, S214, T231 and S235 before the repeats; S396, S404 and S422 after the the repeats. Phosphorylation at these sites tends to disrupt the association between Tau and microtubule. Interestingly, phosphorylation at S199, S202, T205, S396 or S404 also disrupts the association between Tau and the plasma membrane (Arrasate et al., 2000; Maas et al., 2000; Pooler et al., 2012).