User:Madelyn Kasprzak/Sandbox 92021

From Proteopedia

Revision as of 23:40, 2 December 2015

Structure and Function

The human tau protein (Figure 1), encoded by chromosome 17q21, has a natively unfolded protein structure, which contributes to its flexibility and ability to transport via functional microtubules ^[1]. 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). Image:MultipleTauTogether.png

Figure 1. Crystallized structure of tau protein on PYMOL. Each distinct color represents a separate tau protein.

Image:SingularTau.png

Figure 2. Cystallized structure of tau protein on PYMOL. Single tau protein bent onto microtubule (not depicted here). The red areas demonstrate small alpha helices while the green areas demonstrate partially folded peptide sequences.

Additionally, tau (Figure 2) 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 (Figure 3).

AlternativeSplicing 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).

Chemical Alternations 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.

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 (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). This phosphorylation is greatly increased when mutations of the tau protein are present (Alonso et al., 2004). 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 (Figure 3). Thus, any abnormalities in the protein’s phosphorylation state may contribute to neurodegeneration, as described below (Rodríguez-Martin et al., 2013).

Image:PhosporylationTau.png

Figure 3. Common phosphorylation sites of wild type and mutated tau protein (Alonso et al., 2004).

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 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).

Image:AggregationOfTau.png

Figure 4. Demonstration of Tau protein aggregation and breakdown of microtubules from diseased neurons (Pavlova et al., 2009).

References

Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012 Jul;7(1):a006247. PMID: 22762014

Alonso, A. C., Mederlyova, A., Novak, M., Grundke-Iqbal, I., & Iqbal, K. 2004. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. The Journal of Biological Chemistry, 279, 34873-34881.

Biernat, J., Mandelkow, E. M., Schroter, C., Lichtenberg-Kraag, B., Steiner, B., Berling, B., Meyer, H., Mercken, M., Vandermeeren, A., Goedert, M., & Mandelkow, E. 1992. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO Journal, 11(4), 1593-1597.

Buée, L., Bussiere, T., Buée-Scherrer, V., Delacourte, A., & Hof, P. R. 2000. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Research Reviews, 33(1), 95-130.

Butner, K., & Kirschner, M. W. 1991. Tau protein binds to microtubules through a flexible array of distributed weak sites. The Journal of Cell Biology, 115(3), 717-730.

Cohen, T. J., Friedmann, D., Hwang, A. W., Marmorstein, R., & Lee, V. M. 2013. The microtubule-associated tau protein has intrinsic acetyltransferase activity. Nature Structural & Molecular Biology, 20(6), 756-762.

Ishizawa, T., Mattila, P., Davies, P., Wang, D., & Dickson, D. W. 2003. Colocalization of tau and alpha‐synuclein epitopes in lewy bodies. Journal of Neuropathology & Experimental Neurology, 62(4), 389-397.

Kadavath, H., Hofele, R., Biernat, J., Kumar, S., Tepper, K., Urlaub, H., Mandelkow, E., & Zweckstetter, M. 2015. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proceedings of the National Academy of Sciences, 112(24), 7501-7506.

Kolarova, M., Garcia-Sierra, F., Bartos, A., Ricny, J., & Ripova, D. 2012. Structure and pathology of tau protein in Alzheimer disease. International Journal of Alzheimer's Disease, 2012(1), 1-13.

Lansdall, C. 2014. An effective treatment for Alzheimer's disease must consider both amyloid and tau. Bioscience Horizons, 7(1), 1-11.

Lei, P., Ayton, S., Finkelstein, D. I., Adlard, P. A., Masters, C. L., & Bush, A. I. 2010. Tau protein: relevance to Parkinson’s disease. International Journal of Biochemistry and Cell Biology, 42(11), 1775-1778.

Mandelkow, E. M. & Mandelkow, E. 2012. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor Perspective in Medicine, 2, a006247.

Mietelska-Porowska, A., Wasik, U., Goras, M., Filipek, A., & Niewiadomska, G. 2014. Tau protein modifications and interactions: their role in function and dysfunction. International Journal of Molecular Sciences, 15(3), 4671-4713.

Pavlova, A., McCarney, E. R., Peterson, D. W., Dahlquist, F. W., Lew, J., & Han, S. 2009. Site-specific dynamic nuclear polarization of hydration water as a generally applicable approach to monitor protein aggregation. Physical Chemistry Chemical Physics, 11(31), 6833-6839.

The PyMOL Molecular Graphics System, Version 1.7.4 Schrödinger, LLC.

Rodríguez-Martín, T., Cuchillo-Ibáñez, I., Noble, W., Nyenya, F., Anderton, B. H., & Hanger, D. P. 2013. Tau phosphorylation affects its axonal transport and degradation. Neurobiology of Aging, 34(9), 2146-2157.

Ross, C. A. & Poirier, M. A. 2004. Protein aggregation and neurodegenerative disease. Nature Medicine, 10, S10-S17.

Schweers, O., Schönbrunn-Hanebeck, E., Marx, A., & Mandelkow, E. 1994. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. Journal of Biological Chemistry, 269(39), 24290-24297.