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当代阿耳茨海默病研究

Editor-in-Chief

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

Research Article

在人类Tau蛋白的2在人类Tau蛋白的27个赖氨酸残基中的乙酰化模拟物的Silico评价7个赖氨酸残基中的乙酰化模拟物的Silico评价

卷 16, 期 5, 2019

页: [379 - 387] 页: 9

弟呕挨: 10.2174/1567205016666190321161032

价格: $65

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摘要

背景:各种神经退行性疾病,包括阿尔茨海默病(AD),与脑损伤中异常的过度磷酸化微管相关蛋白tau积聚有关。最近的研究集中于由另一种翻译后修饰(PTM)引起的毒性,即tau蛋白的赖氨酸(K)残基的乙酰化。因为有许多乙酰化位点,一些研究引入了使用从赖氨酸到谷氨酰胺(Q)的氨基酸取代的tau乙酰化的模拟物。然而,人类tau蛋白含有20多个乙酰化位点;因此,研究乙酰化tau的影响是困难的。 目的:本文,作者在计算机上使用SIFT,PolyPhen-2和PROVEAN评估乙酰化效应,其可以基于tau同种型中的序列同源性或蛋白质结构来估计氨基酸取代的影响。此外,他们还研究了使用华尔兹对tau蛋白淀粉样蛋白形成的27种乙酰化作用。 结果:15种乙酰化模拟物估计是最有害的,这表明在人类tau蛋白中可能存在新的致病性乙酰化位点。有趣的是,根据同种型的类型,乙酰化模拟物的有害作用是不同的。此外,预测所有乙酰化模拟物是人tau蛋白的密码子274-279处淀粉样蛋白形成的区域。值得注意的是,密码子311(K311Q)的乙酰化模拟诱导了位于人tau蛋白的密码子306-311上的另外的淀粉样蛋白区域的形成。 结论:据我们所知,这是第一次同时对27种人类tau蛋白残基的乙酰化状态进行计算机内评估。

关键词: 计算机分析,tau,阿尔茨海默病,乙酰化,模拟,神经退行性疾病。

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[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).

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