The multifunctional poly(A)-binding protein (PABP) 1 is subject to extensive dynamic post-translational modification, which molecular modelling suggests plays an important role in co-ordinating its activities.
The multifunctional poly(A)-binding protein (PABP) 1 is subject to extensive dynamic post-translational modification, which molecular modelling suggests plays an important role in co-ordinating its activities.
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DOI：
10.1042/bj20111474
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Gray NK
中科院分区：
文献类型：
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作者：
Brook M;McCracken L;Reddington JP;Lu ZL;Morrice NA;Gray NK
PABP1[聚(A)结合蛋白1]是mRNA翻译和稳定性的中央调节因子，是miRNA(MicroRNA)介导的调节和无义介导的衰退所必需的。许多蛋白质以及RNA的相互作用奠定了它的多功能性质；然而，尚不清楚它的不同活动是如何协调的，因为许多伙伴通过重叠的结合位点相互作用。在本研究中，我们发现人类PABP1经历了精心的翻译后修饰，发现了分布在整个功能域的14个修饰，除了一个外，所有这些修饰都在小鼠中保守。有趣的是，PABP1包含谷氨酸和天冬氨酸甲基化，真核生物中未知功能的修饰，以及赖氨酸和精氨酸甲基化，以及赖氨酸乙酰化。后者显著改变PABP1的等电点，这一效应也在细胞周期中观察到，表明不同的生物过程/刺激可以调节其修饰状态，尽管PABP1可能也存在于细胞内差异修饰的亚群中。两个赖氨酸残基被不同地乙酰化或甲基化，揭示了PABP1可能是第一个利用甲基化/乙酰化开关的细胞质蛋白。利用现有结构进行建模表明，这些修饰参与调节与单个PAM2(PABP相互作用基序2)蛋白的相互作用，表明PABP1修饰状态与调节细胞质中mRNA命运的不同mRNP(信使核糖核蛋白)复合体的形成之间存在直接联系。
PABP1 [poly(A)-binding protein 1] is a central regulator of mRNA translation and stability and is required for miRNA (microRNA)-mediated regulation and nonsense-mediated decay. Numerous protein, as well as RNA, interactions underlie its multi-functional nature; however, it is unclear how its different activities are co-ordinated, since many partners interact via overlapping binding sites. In the present study, we show that human PABP1 is subject to elaborate post-translational modification, identifying 14 modifications located throughout the functional domains, all but one of which are conserved in mouse. Intriguingly, PABP1 contains glutamate and aspartate methylations, modifications of unknown function in eukaryotes, as well as lysine and arginine methylations, and lysine acetylations. The latter dramatically alter the pI of PABP1, an effect also observed during the cell cycle, suggesting that different biological processes/stimuli can regulate its modification status, although PABP1 also probably exists in differentially modified subpopulations within cells. Two lysine residues were differentially acetylated or methylated, revealing that PABP1 may be the first example of a cytoplasmic protein utilizing a ‘methylation/acetylation switch’. Modelling using available structures implicates these modifications in regulating interactions with individual PAM2 (PABP-interacting motif 2)-containing proteins, suggesting a direct link between PABP1 modification status and the formation of distinct mRNP (messenger ribonucleoprotein) complexes that regulate mRNA fate in the cytoplasm.