Genome-wide analysis of histidine repeats reveals their role in the localization of human proteins to the nuclear speckles compartment.
Genome-wide analysis of histidine repeats reveals their role in the localization of human proteins to the nuclear speckles compartment.
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DOI：
10.1371/journal.pgen.1000397
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
de la Luna S
中科院分区：
文献类型：
--
作者：
Salichs E;Ledda A;Mularoni L;Albà MM;de la Luna S
单氨基酸重复序列在真核生物中普遍存在，尽管许多这样的序列的作用仍然知之甚少。我们已经对人类基因组中含有均聚组氨酸片段的蛋白质进行了全面分析，并确定了86种含有5个或更多组氨酸片段的人类蛋白质。它们中的大多数被赋予与DNA和RNA相关的功能，此外，在大脑和/或神经系统发育中表达的蛋白质过多。对它们的亚细胞定位的分析表明，所鉴定的22种核蛋白中有15种积累在称为核斑点的核亚区室中。当组氨酸重复缺失时，这种定位丢失，并且显著地，没有组氨酸重复的密切相关的旁系同源蛋白也不能定位于核斑点。因此，组氨酸段似乎直接参与将蛋白质靶向该隔室。去除DNA结合结构域或用RNA聚合酶II抑制剂处理诱导几种含多组氨酸的蛋白质从核质重新定位到核斑点。这些发现强调了转录位点和核斑点之间的动态关系。因此，我们将组氨酸重复序列定义为核斑点的一种新的靶向信号，我们认为这些重复序列是基因重复序列中产生进化多样性的一种方式。这些数据有助于我们更好地理解蛋白质中单个氨基酸重复序列的生理作用。单氨基酸重复序列在真核生物蛋白质中很常见。其中一些与人类的发育和神经退行性疾病有关，表明它们发挥着重要的功能。然而，许多这些重复的作用是未知的。在这里，我们研究了组氨酸重复序列从生物信息学以及功能的角度来看。我们发现，人类基因组中只有86种蛋白质含有5个或更多组氨酸，并且这些蛋白质中的大多数具有与RNA合成相关的功能。当研究这些蛋白质在细胞中的定位时，我们发现相当大的比例通过组氨酸重复序列积累在被称为核斑点的亚核细胞器中。这是一个与RNA合成和加工相关的蛋白质积累的结构。在某些情况下，定位是瞬时的，并且取决于细胞的转录要求。我们的发现很重要，因为它们确定了组氨酸残基延伸的共同细胞功能，并且它们支持组氨酸重复有助于产生进化多样性的概念。最后，考虑到一些组氨酸延伸的蛋白质是基本发育过程中的关键元素，这些重复序列的变异预计会导致人类疾病。
Single amino acid repeats are prevalent in eukaryote organisms, although the role of many such sequences is still poorly understood. We have performed a comprehensive analysis of the proteins containing homopolymeric histidine tracts in the human genome and identified 86 human proteins that contain stretches of five or more histidines. Most of them are endowed with DNA- and RNA-related functions, and, in addition, there is an overrepresentation of proteins expressed in the brain and/or nervous system development. An analysis of their subcellular localization shows that 15 of the 22 nuclear proteins identified accumulate in the nuclear subcompartment known as nuclear speckles. This localization is lost when the histidine repeat is deleted, and significantly, closely related paralogous proteins without histidine repeats also fail to localize to nuclear speckles. Hence, the histidine tract appears to be directly involved in targeting proteins to this compartment. The removal of DNA-binding domains or treatment with RNA polymerase II inhibitors induces the re-localization of several polyhistidine-containing proteins from the nucleoplasm to nuclear speckles. These findings highlight the dynamic relationship between sites of transcription and nuclear speckles. Therefore, we define the histidine repeats as a novel targeting signal for nuclear speckles, and we suggest that these repeats are a way of generating evolutionary diversification in gene duplicates. These data contribute to our better understanding of the physiological role of single amino acid repeats in proteins. Single amino acid repeats are common in eukaryotic proteins. Some of them are associated with developmental and neurodegenerative disorders in humans, suggesting that they play important functions. However, the role of many of these repeats is unknown. Here, we have studied histidine repeats from a bioinformatics as well as a functional point of view. We found that only 86 proteins in the human genome contain stretches of five or more histidines, and that most of these proteins have functions related with RNA synthesis. When studying where these proteins localize in the cell, we found that a significant proportion accumulate in a subnuclear organelle known as nuclear speckles, via the histidine repeat. This is a structure where proteins related to the synthesis and processing of RNA accumulate. In some cases, the localization is transient and depends on the transcriptional requirements of the cell. Our findings are important because they identify a common cellular function for stretches of histidine residues, and they support the notion that histidine repeats contribute to generate evolutionary diversification. Finally, and considering that some of the proteins with histidine stretches are key elements in essential developmental processes, variation in these repeats would be expected to contribute to human disease.
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影响因子：
5.3
作者：
Aranda, Sergi;Alvarez, Monica;de la Luna, Susana
通讯作者：
de la Luna, Susana
影响因子：
14.9
作者：
Flicek P;Aken BL;Beal K;Ballester B;Caccamo M;Chen Y;Clarke L;Coates G;Cunningham F;Cutts T;Down T;Dyer SC;Eyre T;Fitzgerald S;Fernandez-Banet J;Gräf S;Haider S;Hammond M;Holland R;Howe KL;Howe K;Johnson N;Jenkinson A;Kähäri A;Keefe D;Kokocinski F;Kulesha E;Lawson D;Longden I;Megy K;Meidl P;Overduin B;Parker A;Pritchard B;Prlic A;Rice S;Rios D;Schuster M;Sealy I;Slater G;Smedley D;Spudich G;Trevanion S;Vilella AJ;Vogel J;White S;Wood M;Birney E;Cox T;Curwen V;Durbin R;Fernandez-Suarez XM;Herrero J;Hubbard TJ;Kasprzyk A;Proctor G;Smith J;Ureta-Vidal A;Searle S
通讯作者：
Searle S
软骨寡聚基质蛋白（COMP）基因的三核苷酸扩增突变
影响因子：
3.5
作者：
Délot, E;King, LM;Cohn, DH
通讯作者：
Cohn, DH
DOI：
10.1002/ajmg.10221
发表时间：
2002-03-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Brown, LY;Hodge, SE;Brown, S
通讯作者：
Brown, S
影响因子：
4.8
作者：
Becker, W;Weber, Y;Joost, HG
通讯作者：
Joost, HG