KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification.
KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification.
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DOI：
10.1038/ncomms13227
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发表时间：
2016-10-31
影响因子：
16.6
通讯作者：
Tora, Laszlo
中科院分区：
文献类型：
--
作者：
Fournier, Marjorie;Orpinell, Meritxell;Grauffel, Cedric;Scheer, Elisabeth;Garnier, Jean-Marie;Ye, Tao;Chavant, Virginie;Joint, Mathilde;Esashi, Fumiko;Dejaegere, Annick;Gonczy, Pierre;Tora, Laszlo
赖氨酸乙酰化是一种广泛的翻译后修饰，调节着多种生物过程。为了表征人赖氨酸乙酰转移酶KAT2A （GCN5）和KAT2B （PCAF）的细胞功能，我们采用散弹枪蛋白质组学方法测定了它们的乙酰化酶。新发现的KAT2A/2B底物之一是polo样激酶4 (PLK4)，它是中心体复制的关键调节因子。我们证明KAT2A/2B在K45和K46残基上乙酰化PLK4激酶结构域。分子动力学模型表明K45/K46乙酰化通过将激酶转移到非活性构象而损害激酶活性。因此，PLK4的活性在其激酶结构域体外乙酰化后降低。此外，PLK4 K45R/K46R突变体在细胞中的过表达不会导致中心体过扩增，这与野生型PLK4不同。我们还发现，KAT2A/ 2b -乙酰转移酶活性受损会导致PLK4磷酸化降低和细胞中中心体数量过多。总体而言，我们的研究确定了全球人类KAT2A/2B乙酰化，并发现PLK4的KAT2A/2B乙酰化可阻止中心体扩增。乙酰转移酶KAT2A和KAT2B是转录、细胞周期进程和DNA修复的重要调节因子。在这里，作者描述了一个KAT2A/ 2b依赖的乙酰化体，并表明蛋白激酶PLK4的乙酰化有助于中心体数量的调节。
Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation. Accordingly, PLK4 activity is reduced upon in vitro acetylation of its kinase domain. Moreover, the overexpression of the PLK4 K45R/K46R mutant in cells does not lead to centrosome overamplification, as observed with wild-type PLK4. We also find that impairing KAT2A/2B-acetyltransferase activity results in diminished phosphorylation of PLK4 and in excess centrosome numbers in cells. Overall, our study identifies the global human KAT2A/2B acetylome and uncovers that KAT2A/2B acetylation of PLK4 prevents centrosome amplification. The acetyltransferases KAT2A and KAT2B are essential regulators of transcription, cell cycle progression and DNA repair. Here the authors describe a KAT2A/2B-dependent acetylome, and show that acetylation of the protein kinase PLK4 contributes to the regulation of centrosome number.
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DOI：
10.1002/prot.340040208
发表时间：
1988-01-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
BRUNGER, AT;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
14.9
作者：
Eswar, N;John, B;Sali, A
通讯作者：
Sali, A
影响因子：
14.9
作者：
Hornbeck PV;Kornhauser JM;Tkachev S;Zhang B;Skrzypek E;Murray B;Latham V;Sullivan M
通讯作者：
Sullivan M
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
11.4
作者：
Brand, M;Moggs, JG;Tora, L
通讯作者：
Tora, L