Structural and functional diversity of the microbial kinome.
Structural and functional diversity of the microbial kinome.
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DOI：
10.1371/journal.pbio.0050017
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发表时间：
2007-03
期刊：
影响因子：
9.8
通讯作者：
Manning G
中科院分区：
文献类型：
--
作者：
Kannan N;Taylor SS;Zhai Y;Venter JC;Manning G
真核蛋白激酶（ePK）结构域介导了真核生物中大多数复杂事件的信号传导和协调。相比之下，大多数细菌信号被认为是通过结构不相关的组氨酸激酶发生的，尽管在细菌中已知一些epk样激酶（ELKs）和小分子激酶。我们对全球海洋采样（GOS）数据集的分析表明，ELKs与组氨酸激酶一样普遍，并且可能在原核生物行为中发挥同样重要的作用。通过结合GOS和公共数据库，我们发现ePK只是建立在共同蛋白激酶样（PKL）折叠上的多种酶超家族的一个子集。我们探索了这个巨大的系统发育和功能空间，以阐明这个超家族的古老进化，其机制核心，以及其观察到的多样性的结构基础。我们编目了27,677个epk和18,699个elk，并将它们分为20个高度不同的家族，其已知成员具有调节功能。GOS数据使ELK序列的数量增加了两倍以上，并使新家族的发现和所有ELK的分类和分析成为可能。家族之间和家族内部的比较揭示了跨家族高度保守的10个关键残基。然而，在一个或另一个家族中，除了一个残基外，其余的残基都被消除了，这表明具有很大的功能可塑性。我们表明，两个家族中催化赖氨酸的缺失是通过涉及其他关键基元的不同机制来补偿的。这种多样化的超家族为进一步的酶进化结构和功能分析提供了模型。序列数据库的巨大增长使得通过与其相关序列的比较来表征每个蛋白质序列成为可能。序列比较可以揭示定义蛋白质家族的关键保守功能基序和特定于单个亚家族的变异，从而用其进化背景修饰任何蛋白质序列。受全球海洋调查项目大量序列的启发，作者深入研究了蛋白激酶样（PKL）超家族。真核蛋白激酶（ePKs）是真核细胞生物学的杰出控制者，也是研究得最好的酶之一。相比之下，它们的原核亲缘生物却鲜为人知。作者希望能够更好地表征和理解这些原核酶，同时，通过对比，为真核蛋白激酶的核心机制提供见解。作者使用远程同源方法，并在他们的发现基础上检测了超过45,000个PKL序列。它们分为20个主要家族，epk只是其中之一。10个残基在这些家族之间是保守的：6个已知在催化中是重要的，但另外4个，包括3个在epk中高度保守的，尽管它们的古老保存，但仍然知之甚少。广泛的家族特异性特征被发现，包括在一个或另一个家族中，除了十个关键残基中的一个外，所有的残基都令人惊讶地丢失了。作者探索了这些缺失，并发现了几个案例，其中一个关键基序的变化替代了另一个关键基序的变化，证明了这些序列的可塑性。类似的方法可以用来更好地理解任何其他家族的蛋白质序列。超过45,000种激酶，包括GOS探险队发现的16,000种，被分为20个不同的家族。这种大规模的序列比较揭示了真核蛋白激酶的结构灵活性，有助于解释它们在真核生物中的巨大扩张。
The eukaryotic protein kinase (ePK) domain mediates the majority of signaling and coordination of complex events in eukaryotes. By contrast, most bacterial signaling is thought to occur through structurally unrelated histidine kinases, though some ePK-like kinases (ELKs) and small molecule kinases are known in bacteria. Our analysis of the Global Ocean Sampling (GOS) dataset reveals that ELKs are as prevalent as histidine kinases and may play an equally important role in prokaryotic behavior. By combining GOS and public databases, we show that the ePK is just one subset of a diverse superfamily of enzymes built on a common protein kinase–like (PKL) fold. We explored this huge phylogenetic and functional space to cast light on the ancient evolution of this superfamily, its mechanistic core, and the structural basis for its observed diversity. We cataloged 27,677 ePKs and 18,699 ELKs, and classified them into 20 highly distinct families whose known members suggest regulatory functions. GOS data more than tripled the count of ELK sequences and enabled the discovery of novel families and classification and analysis of all ELKs. Comparison between and within families revealed ten key residues that are highly conserved across families. However, all but one of the ten residues has been eliminated in one family or another, indicating great functional plasticity. We show that loss of a catalytic lysine in two families is compensated by distinct mechanisms both involving other key motifs. This diverse superfamily serves as a model for further structural and functional analysis of enzyme evolution. The huge growth in sequence databases allows the characterization of every protein sequence by comparison with its relatives. Sequence comparisons can reveal both the key conserved functional motifs that define protein families and the variations specific to individual subfamilies, thus decorating any protein sequence with its evolutionary context. Inspired by the massive sequence trove from the Global Ocean Survey project, the authors looked in depth at the protein kinase–like (PKL) superfamily. Eukaryotic protein kinases (ePKs) are the pre-eminent controllers of eukaryotic cell biology and among the best studied of enzymes. By contrast, their prokaryotic relatives are much more poorly known. The authors hoped to both characterize and better understand these prokaryotic enzymes, and also, by contrast, provide insight into the core mechanisms of the eukaryotic protein kinases. The authors used remote homology methods, and bootstrapped on their discoveries to detect more than 45,000 PKL sequences. These clustered into 20 major families, of which the ePKs were just one. Ten residues are conserved between these families: 6 were known to be important in catalysis, but four more—including three highly conserved in ePKs—are still poorly understood, despite their ancient conservation. Extensive family-specific features were found, including the surprising loss of all but one of the ten key residues in one family or another. The authors explored some of these losses and found several cases in which changes in one key motif substitute for changes in another, demonstrating the plasticity of these sequences. Similar approaches can be used to better understand any other family of protein sequences. Over 45,000 kinases, including 16,000 identified in the GOS expedition, were classified into 20 distinct families. This massive sequence comparison revealed a structural flexibility within eukaryotic protein kinases that helps explain their huge expansion in eukaryotes.
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影响因子：
4.5
作者：
Goldberg, Jonathan M.;Manning, Gerard;Liu, Allen;Fey, Petra;Pilcher, Karen E.;Xu, Yanji;Smith, Janet L.
通讯作者：
Smith, Janet L.
影响因子：
3.6
作者：
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通讯作者：
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影响因子：
14.9
作者：
Haft, DH;Loftus, BJ;White, O
通讯作者：
White, O
影响因子：
2.9
作者：
Aimes, RT;Hemmer, W;Taylor, SS
通讯作者：
Taylor, SS
影响因子：
14.9
作者：
Finn RD;Mistry J;Tate J;Coggill P;Heger A;Pollington JE;Gavin OL;Gunasekaran P;Ceric G;Forslund K;Holm L;Sonnhammer EL;Eddy SR;Bateman A
通讯作者：
Bateman A