Tau protein

Structure and Function

The human tau protein, encoded by chromosome 17q21, has a natively unfolded protein structure, which contributes to its flexibility and ability to stabilize functional microtubules ^[1]. Specifically, its primary structure, consisting of , is highly hydrophilic compared to other cytosolic proteins ^[1]. It has a predominantly acidic N-terminal region, a proline-rich middle region, and a relatively neutral C-terminal region ^[1].

Additionally, tau has a transient secondary structure of α-helices, β-pleated sheets, and a poly-proline II helix ^[1]. Tau does not resemble a globular protein, but has characteristics of a denatured, unfolded protein which contributes to its overall hydrophilicity ^[2]. It can also interact with other tau proteins to form .

See also Structure and dynamics of the microtubule-binding hot-spots on the neuronal protein tau.

Alternative Splicing

Alternative splicing of the human tau gene 17q21 generates several isoform structures, which differ by one or two small inserts in its N-terminal region ^[3]. Although there are 16 exons within the 17q21 gene, exons 4A, 6, and 8 are expressed in peripheral rather than neural tau proteins ^[4]. Alternatively, eight of the exons (1, 4, 5, 7, 9, 11, 12, and 13) are involved in structural aspects of tau ^[4]. Alternative splicing of exons 2, 3, and 10 is responsible for the 6 isoforms of tau ^[3]. These isoforms differ in 3 or 4 tubulin binding domains within the C-terminal region ^[5].

Chemical Alterations

Tau proteins typically undergo post-translational modifications such as O-glycosylation and phosphorylation. O-glycosylation involves the addition of an O-linked N-acetylglucosamine residue on a serine or threonine amino acid adjacent to the proline-rich domain ^[4]. This modification is not fully understood, however it may be involved in interactions with tubulin and degradation of tau proteins ^[4]. Several phosphorylation sites have been identified on mainly serine-proline and threonine-proline amino motifs ^[4]. Tau protein kinases typically catalyze the phosphorylation of tau; however, non-proline directed kinases could also phosphorylate other sites within tau ^[4]. Tau phosphorylation directly affects its ability to bind to microtubules ^[4], as described below.

Tau's Role in Microtubules and Axonal Transport

Tau binds to microtubules and aids in their assembly and stabilization as well as the motor-driven transport of axons ^[6]. Its ability to stabilize microtubules is attributed to repetitive microtubule-binding motifs within its C-terminal region ^[3]. These 18-amino acid repeat domains bind to microtubules through weak interactions such as van der Waals or ionic bonds ^[7]. Specifically, the area in the interregion between repeats 1 and 2 is highly potent in microtubule polymerization ^[5]. Although the repeat domains are similar in structure, they differ in their binding affinities, which is likely attributed to slight differences in their amino acid sequence ^[7]. Their flexibility and lack of binding cooperativity further accentuate the protein’s transient secondary structure ^[7].

The phosphorylation state of tau directly affects proper assembly and stabilization of microtubules ^[5]. Phosphorylation is greatly increased when mutations of the tau protein are present ^[8]. Phosphate groups on a highly phosphorylated tau may disrupt non-covalent interactions between the protein and microtubules, which may reduce tubulin stability and impair axonal transport. Thus, any abnormalities in the protein’s phosphorylation state may contribute to neurodegeneration, as described below ^[9].

Role of human tau in stabilization of microtubules through tubulin binding domains (blue). Phosphorylation (pink) of tau can directly regulate its interaction with microtubules and its role in axonal transport ^[5]

Disease Relation

Alzheimer’s Disease and Dementia A common abnormality in tau phosphorylation, associated with Alzheimer’s disease, is the phosphorylation of two serine-proline motifs located 199 or 202 amino acids upstream of the microtubule-binding region ^[10]. Phosphorylated helical filaments within these motifs can lead to neurofibrillary tangles, also known as aggregations of tau proteins ^[2]. Lysine acetylation catalyzed by tau autoacetyltransferase activity can also lead to tau aggregation, thereby preventing tau from interacting with microtubules ^[11]. Dysfunction of the neuronal cell, likely caused by tau aggregation, can lead to gradual but steady neurodegeneration, which is correlated with the onset of dementia ^[12]. Tau aggregation may contribute to neuronal loss via cell death in areas of the brain responsible for memory and learning ^[5].

Parkinson’s Disease

Protein aggregation also exists in patients suffering from Parkinson’s disease, specifically within the substantia nigra of the midbrain ^[13]. Immunohistochemical studies reveal that abnormally phosphorylated tau proteins are partially involved in the development of Lewy bodies, protein aggregates, within the substantia nigra ^[14]. Lewy bodies may be involved in the neurodegeneration of dopaminergic neurons within this area ^[13].

3D Structures of tau protein

Tau protein 3D structures