Introduction

The tau protein has been identified across the tree of life [1]. However, to enable scope within discussion, this exploration will mainly focus on human tau isoforms.

Tau belongs to the large Microtubule Associated Protein family (MAPT) and bar basal levels, expression is restricted to neurons of the CNS [2]. The tau protein has multiple roles, however it principally encourages microtubule-assembly and maintains the stability of neural axons [1].

Tau is encoded by the MAPT gene, located on 17q21 with a total of 14 protein-coding exons [1]. Historically 6 tau isoforms were identified, although a further 3 have been recently characterised [1-3]. However, there is some inconsistency as only 8 out of the 9 reported human isoforms can be found in BLAST searching.

The different isoforms (Fig. 2) are formed via complex alternative splicing implicating exons 2, 3 and 10.

Fig. 1 Function of Tau

The domains of tau bind many types of molecules such as actins, microtubules, SH3 domains etc. , suggesting a central role in signalling pathways and cytoskeletal organisation.

The resulting 9 isoforms range from 316-776 amino acids long, with all being expressed throughout the adult nervous system, apart from a specific fetal isoform [3-4]. There is limited secondary structure in tau, forming a random coil polymer; however there appears to be discrepancies in the reported structure [5].

Fig. 2- Tau Isoforms

(A) The longest MAPT mRNA is composed of 14 exons and 2 UTRs , which are alternatively spliced.The R2 MT-domain is encoded by exon 11, which is alternatively spliced and missing between different isoforms such as fetal-tau.

(B) The resulting 9 human tau isoforms. Fetal-tau is only expressed in fetal brain tissue.

Adapted from [2]

Tau is a tripartite molecule containing variable N-terminal domains, a middle proline-rich domain and C-terminal tubulin-binding regions [6]. This tubulin binding region contains either three or four repeat domains (R1-R4) encoded by exons 9-12. These repeats contain 18 conserved amino-acids, with the same sequence present in the familial MAP2 protein [6]. The repeats are separated by 13-14 (less conserved) amino acid linkers [1]. Based on the widely agreed ‘jaws model’ the flanking regions strongly bind to microtubules, correctly positioning tau whilst the repeats catalyse microtubule assembly. This has been experimentally supported by NMR spectroscopy [7].

Furthermore tau proteins can bind actin filaments thereby linking microtubules to other cytoskeletal components [8]. The identification of the Src family receptor non-tyrosine kinase SH3 binding domain –PXXP- in tau, has implicated tau with binding to members of this family including fyn [9]. Therefore, this suggests that tau has a role in this Src family receptor signalling pathway and thus modifies cell shape by binding to sub-membranous actin cytoskeleton [9].

In addition to alternative splicing tau proteins are extensively post-translationally modified; phosphorylation being particularly prominent [9]. Phosphorylation decreases tau-stimulated microtubule polymerization efficiency and binding [1]. Multiple phosphorylation sites have been identified (79 Ser/Thr phosphorylation sites in the longest isoform) particularly Ser-Pro or Thr-Pro motifs [1]. These are phosphorylated by proline directed kinases including MAP and GSK [10; 11]. Additionally, MARK2 is heavily implicated with non-proline associated site phosphorylation [12]. Incidentally inappropriate tau phosphorylation has been associated with multiple pathologies, known as tauopathies, implicating tau as a clinically important protein to be explored [1].

References