Tau Domains and Interactions

 

 

This page explores and describes the structure and function of each of the domains identified by our BLASTP and PFAM searches of Tau isoforms.

 

 

Functional Domains

 

Six out of nine tau isoforms exist in the human brain; Tau B-F in the adult brain and fetal-tau in the developing fetus. These six isoforms vary in the number of repeats at the C-terminal half, and the number of inserts at the N-terminal half. When run on polyacrylamide gel electrophoresis in presence of sodium dodecyl sulphate it was observed that the 6 isoforms range from 45 to 65 kDa. Exon 10 encodes one of the four microtubule-binding repears.If the exon is present the protein contains 4 repeats and is referred to 4R, but if it is spliced out the molecule is termed 3R. Exons 2 and 3 are found at the N-terminus, and tau isoforms are classified based on the presence or absence of these. If both exons are present tau is termed 2N, if the only one is present tau is termed 1N, and 0N in the absence of both [8,10].

 

The domains of Tau are thus defined on the basis of their microtubule interaction and/or their amino acid character. The Tau protein binds  microtubule through the repeats and their flanking regions. Upon binding, the N-terminal portion (<150 residues) projects from the microtubule surface. For this reason, the N-terminal portion is called the projection domain, which may bind to other cellular components such as the plasma membrane. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that Tau functions as a linker protein between the two [4].

 

 

 

 

 

 

 

 

 

Fig 1. functional domains of Tau Protein.

As shown in Figure 1, human Tau isoform. Most of the chain is unfolded, with a few short and transient elements of secondary structure [1] [8].

 

Phosphorylation Sites

 

The longest isoform, Tau-F (441AA) contains approximately 60 potential phosphorylation sites. Among them, five are tyrosine residues, conserved in all isoforms. These are located at positions 18, 29, 197, 310 and 394. A tyrosine kinase called Fyn preferentially targets Y18, which is phosphorylated in Alzheimer's patients and at early developmental stages of mice, but not in healthy adults. In Alzheimer's Disease (AD), significant number of Tau residues are phosphorylated. The phosphorylation of Y18, however, does not significantly alter microtubule binding and stability [5,9].

 

Y394 is also phosphorylated in both AD brain and fetal brain. This phosphorylation again has little effect on the binding of microtubules. Y394 unlike Y18, is targeted by tyrosine kinase c-Abl. Recent work has demonstrated that these residues are phosphorylated in the fetus, indicating that their phosphorylation has normal functions during development. In fact, it has been observed that Tau is phosphorylated to a high degree in the fetal brain, but phosphorylated minimally in healthy adult brain [3,8].

 

Projection domain

 

The N-terminal part of the Tau protein is referred to as the projection domain as it projects from the microtubule surface where it can interact with the plasma membrane and other cytoskeletal elements. In fact, projection domains of Tau determine the spacing between microtubule in axon and may increase axonal diameter. Thus, Tau acts as a mediator between microtubules and plasma membrane. Located in the N-terminal part of the Tau protein, there is a proline-rich region containing several P-X-X-P motifs. This motif is known to interact with proteins containing SH3 domain. An important example is Fyn, the enzyme catalysing tyrosine phosphorylation [3,6].

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig. 2. Schematic diagram of the functional domains of the longest tau isoform

The projection domain, containing acidic and proline-rich regions, is  involved in signal transduction pathways by interacting with molecules like Src-kinases and PLC-γ. The C-terminus regulates the rate of microtubule polymerisation, and modulates binding to other proteins such as Protein Phosphatase 2A (PP2A)

Adapted from [5].

 

 

Microtubule Assembly Domain

 

Tau proteins bind microtubules using microtubule-binding repeats in their C-terminal part. The three repeat (3R) or four repeat (4R) domains, depend on alternative splicing of exon 10 encoding the second repeat (2R). Tau 4R isoforms have greater microtubule stabilising ability than 3R isoforms. Only 3R isoform is expressed during fetal development, whereas adult brain normally has a ratio of 1:1 for 3R and 4R isoforms [2]. Deregulation of this 1:1 ratio often results in various tauopathies.

 

 

 

 

 

 

References:

[1] http://www.ncbi.nlm.nih.gov/pubmed/8068626

[2] http://www.sciencedirect.com/science/article/pii/0896627389900500

[3] http://www.ncbi.nlm.nih.gov/pubmed/10967355

[4] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385935/

[5] http://www.ncbi.nlm.nih.gov/pubmed/10967355

[6] http://www.ncbi.nlm.nih.gov/pubmed/3121601

[7] http://www.ncbi.nlm.nih.gov/pubmed/1420178

[8] http://www.web-books.com/eLibrary/Medicine/Neurological/Alzheimer_Tau.html

[9] http://www.ncbi.nlm.nih.gov/pubmed/21388709/

[10] http://www.ncbi.nlm.nih.gov/pubmed/11837744