Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

In Silico Evaluation of Acetylation Mimics in the 27 Lysine Residues of Human Tau Protein

Author(s): Yong-Chan Kim and Byung-Hoon Jeong*

Volume 16, Issue 5, 2019

Page: [379 - 387] Pages: 9

DOI: 10.2174/1567205016666190321161032

Price: $65

Abstract

Background: Various neurodegenerative diseases, including Alzheimer’s disease (AD), are related to abnormal hyperphosphorylated microtubule-associated protein tau accumulation in brain lesions. Recent studies have focused on toxicity caused by another post-translational modification (PTM), acetylation of the lysine (K) residues of tau protein. Because there are numerous acetylation sites, several studies have introduced mimics of tau acetylation using amino acid substitutions from lysine to glutamine (Q). However, human tau protein contains over 20 acetylation sites; thus, investigation of the effects of an acetylated tau is difficult.

Objective: Here, the authors in silico evaluated acetylation effects using SIFT, PolyPhen-2 and PROVEAN which can estimate the effects of amino acid substitutions based on the sequence homology or protein structure in tau isoforms. In addition, they also investigated 27 acetylation effects on the amyloid formation of tau proteins using Waltz.

Results: 15 acetylation mimics were estimated to be the most detrimental, which indicates that there may be novel pathogenic acetylation sites in the human tau protein. Interestingly, the deleterious effect of acetylation mimics was different according to the type of isoforms. Furthermore, all acetylation mimics were predicted to be a region of amyloid formation at the codons 274-279 of human tau protein. Notably, acetylation mimic of codon 311 (K311Q) induced the formation of an additional amyloid region located on codons 306-311 of the human tau protein.

Conclusion: To the best of our knowledge, this is the first simultaneous in-silico evaluation of the acetylation state of 27 human tau protein residues.

Keywords: In-silico analysis, tau, Alzheimer's disease, acetylation, mimic, neurodegenerative diseases.

Next »
[1]
Simic G, Babic Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milosevic N, et al. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 6(1): 6. (2016).
[2]
Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24(4): 277-95. (2004).
[3]
Probst A, Tolnay M, Langui D, Goedert M, Spillantini MG. Pick’s disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol 92(6): 588-96. (1996).
[4]
Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 15(23): 2321-8. (2008).
[5]
Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW. Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739(2-3): 216-23. (2005).
[6]
Brion JP, Anderton BH, Authelet M, Dayanandan R, Leroy K, Lovestone S, et al. Neurofibrillary tangles and tau phosphorylation. Biochem Soc Symp 67: 81-8. (2001).
[7]
Bray N. Neurodegenerative disease Targeting tau acetylation attenuates neurodegeneration. Nat Rev Drug Discov 14(11): 748-9. (2015).
[8]
Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2: 252. (2011).
[9]
Grinberg LT, Wang X, Wang C, Sohn PD, Theofilas P, Sidhu M, et al. Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125(4): 581-93. (2013).
[10]
Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21(10): 1154-62. (2015).
[11]
Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67(6): 953-66. (2010).
[12]
Cook C, Stankowski JN, Carlomagno Y, Stetler C, Petrucelli L. Acetylation: a new key to unlock tau’s role in neurodegeneration. Alzheimers Res Ther 6(3): 29. (2014).
[13]
Kamieniarz K, Schneider R. Tools to tackle protein acetylation. Chem Biol 16(10): 1027-9. (2009).
[14]
Tracy TE, Sohn PD, Minami SS, Wang C, Min SW, Li Y, et al. Acetylated tau obstructs kibra-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90(2): 245-60. (2016).
[15]
Gorsky MK, Burnouf S, Dols J, Mandelkow E, Partridge L. Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo. Sci Rep 6: 22685. (2016).
[16]
Gorsky MK, Burnouf S, Sofola-Adesakin O, Dols J, Augustin H, Weigelt CM, et al. Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity. Sci Rep 7(1): 9984. (2017).
[17]
Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nat Protoc 11(1): 1-9. (2016).
[18]
Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7: Unit7 20 (2013).
[19]
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31(16): 2745-7. (2015).
[20]
Oliveberg M. Waltz, an exciting new move in amyloid prediction. Nat Methods 7(3): 187-8. (2010).
[21]
Kadavath H, Hofele RV, Biernat J, Kumar S, Tepper K, Urlaub H, et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci USA 112(24): 7501-6. (2015).
[22]
Breuzard G, Hubert P, Nouar R, De Bessa T, Devred F, Barbier P, et al. Molecular mechanisms of Tau binding to microtubules and its role in microtubule dynamics in live cells. J Cell Sci 126(Pt 13): 2810-9. (2013).
[23]
Elie A, Prezel E, Guerin C, Denarier E, Ramirez-Rios S, Serre L, et al. Tau co-organizes dynamic microtubule and actin networks. Sci Rep 5: 9964. (2015).
[24]
Dakal TC, Kala D, Dhiman G, Yadav V, Krokhotin A, Dokholyan NV. Predicting the functional consequences of non-synonymous single nucleotide polymorphisms in IL8 gene. Sci Rep 7(1): 6525. (2017).
[25]
Liu YH, Li CG, Zhou SF. Prediction of deleterious functional effects of non-synonymous single nucleotide polymorphisms in human nuclear receptor genes using a bioinformatics approach. Drug Metab Lett 3(4): 242-86. (2009).
[26]
Wang LL, Li Y, Zhou SF. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Drug Metab Dispos 37(5): 977-91. (2009).
[27]
Kim YC, Jeong MJ, Jeong BH. The first report of genetic variations in the chicken prion protein gene. Prion 12(3-4): 197-203. (2018).
[28]
Yun CH, Jeong BH. Calcium homeostasis modulator 1 (CALHM1) polymorphisms in cattle. Pesq Vet Bra (37): 582-86 (2017).
[29]
Inouye H, Sharma D, Goux WJ, Kirschner DA. Structure of core domain of fibril-forming PHF/Tau fragments. Biophys J 90(5): 1774-89. (2006).
[30]
Ganguly P, Do TD, Larini L, LaPointe NE, Sercel AJ, Shade MF, et al. Tau assembly: the dominant role of PHF6 (VQIVYK) in microtubule binding region repeat R3. J Phys Chem B 119(13): 4582-93. (2015).
[31]
Kellogg EH, Hejab NMA. Poepsel, Downing KH, DiMaio F, Nogales E. Near-atomic model of microtubule-tau interactions. Science 360(6394): 1242-6. (2018).

Rights & Permissions Print Cite
Article Metrics
71
20
1
2
© 2024 Bentham Science Publishers | Privacy Policy