User:Madelyn Kasprzak/Sandbox 92021

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Structure and Function

The human tau protein, encoded by chromosome 17q21, has a natively unfolded protein structure, which contributes to its flexibility and mobility (Mandelkow & Mandelkow, 2012). Specifically, its primary structure, consisting of serines, threonines, aspartates, glutamates, lysines, arginines, prolines, and aromatics, is highly hydrophilic compared to other cytosolic proteins (Mandelkow & Mandelkow, 2012). It has a predominantly acidic N-terminal, a proline-rich middle region, and a relatively neutral C-terminal (Mandelkow & Mandelkow, 2012). Additionally, tau has a transient secondary structure of α-helices, β-pleated sheets, and a poly-proline II helix (Mandelkow & Mandelkow, 2012). Tau does not resemble a globular protein, but has characteristics of a denatured, unfolded protein which contributes to its overall hydrophilicity (Schweers et al., 1994). Although tau is not a globular protein, it can interact with other tau proteins to form aggregations.

Disease

Alzheimer’s disease and dementia A common abnormality in tau phosphorylation, associated with Alzheimer’s disease, is the phosphorylation of two serine-proline motifs upstream of the microtubule-binding region (Biernat et al., 1992). Phosphorylated helical filaments within these motifs can lead to neurofibrillary tangles-aggregations of tau proteins (Schweers et al., 1994). Lysine acetylation catalyzed by autoacetyltransferase can also lead to tau aggregation, thereby preventing tau from interacting with microtubules (Cohen et al., 2013). 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 (Kolarova et al., 2012; Kadavath et al., 2015). Tau aggregation may contribute to neuronal loss via cell death in areas of the brain responsible for memory and learning (Kolarova et al., 2012; Lansdall, 2014). Parkinson’s disease Protein aggregation also exists in patients suffering from Parkinson’s disease, specifically within the substantia nigra of the midbrain (Ross, 2004). Immunohistochemical studies reveal that abnormally phosphorylated tau proteins are partially involved in the development of lewy bodies, protein aggregates, within the substantia nigra (Ishizawa et al., 2003). Lewy bodies may be involved in the neurogdegeneration of dopaminergic neurons within this area (Ross, 2004).

Structural highlights

Tau binds to microtubules and aids in their assembly and stabilization as well as the motor-driven transport of axons (Mietelska-Porowska et al., 2014). Its ability to stabilize microtubules is attributed to 4 repetitive microtubule-binding motifs within its C-terminal (Lei et al., 2010). These 18-amino acid repeat domains bind to microtubules through weak interactions such as van der Waals or highly shielded ionic bonds (Butner & Kirschner, 1991). 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 (Butner & Kirschner, 1991). Their flexibility and lack of binding cooperativity further accentuates the protein’s transient secondary structure (Butner & Kirschner, 1991). The phosphorylation state of tau directly affects proper assembly and stabilization of microtubules (Kolarova et al., 2012). Phosphate groups on a highly phosphorylated tau may disrupt non-covalent interactions between the protein and microtubules, which may be detrimental to the formation and stabilization of microtubules. Thus, any abnormalities in the protein’s phosphorylation state may contribute to neurodegeneration, as described below (Martin et al., 2013). Alternative splicing of the human tau gene 17q21 generates several isoform structures, which differ by one or two small inserts in its N-terminal (Lei et al., 2010). Although there are 16 exons within the 17q21 gene, exons 4A, 6, and 8 are expressed in peripheral rather than neural tau proteins (Buée et al., 2000). Alternatively, eight of the exons (1, 4, 5, 7, 9, 11, 12, and 13) are involved in structural aspects of tau (Buée et al., 2000). Alternative splicing of exons 2, 3, and 10 is responsible for the 6 isoforms of tau (Lei et al., 2010). These isoforms differ in 3 or 4 tubulin binding domains within the C-terminal and possibly in several inserts of approximately 29 amino acids in the N-terminal (Kolarova et al., 2012). 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 (Buée et al., 2000). This modification is not fully understood, however it may be involved in interactions with tubulin and degradation of tau proteins (Buée et al., 2000). Approximately 30 phosphorylation sites have been identified on mainly serine-proline and threonine-proline amino motifs (Buée et al., 2000). Non-proline directed kinases could also phosphorylate other sites within tau (Buée et al., 2000). Tau phosphorylation directly affects its ability to bind to microtubules (Buée et al., 2000), as described below.

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