Are β‐thymosins WH2 domains?
Are β‐thymosins WH2 domains?
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β-胸腺素是 WH2 结构域吗？
DOI：
10.1016/j.febslet.2004.07.038
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发表时间：
2004
期刊：
影响因子：
3.5
通讯作者：
John Edwards
中科院分区：
文献类型：
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作者：
John Edwards
在他们的综述“WH 2结构域：肌动蛋白单体的小型通用适配器”中，Paunola et al. [1]注意到肌动蛋白结合序列的两个家族的成员之间的序列相似性，WH 2结构域和b-胸腺素。作者通过将WH 2结构域的原始定义从18个残基扩展到35个残基，将两者表示为一个家族。从序列相似性，他们推断出共同的祖先。扩大的WH 2结构域正在流行[2-4]，但缺乏这种关系的证据。b-胸腺素是一种43个残基的肽，作为单体螯合剂在肌动蛋白动力学中发挥作用[5]。最近，已经鉴定了许多含有与单体b-胸腺素非常相似的序列的内部串联重复的蛋白质，首先在果蝇和小杆线虫中[6]，最近在玻璃海鞘、革蜱和Hermissenda中[7]。从果蝇蛋白ciboulot的研究[8]，这些蛋白质在调节肌动蛋白丝的作用可能是不同的单体胸腺素。在单细胞生物中还没有发现b-胸腺素的同系物。WH 2结构域[9]（来自Wiskott-Aldrich同源性2）是18个残基的序列，也赋予肌动蛋白结合，已知仅作为较大蛋白质的模块部分，但广泛分布于胚胎发育中，存在于细菌（蒙大拿立克次氏体和副溶血性弧菌中的假设蛋白质）、节肢动物的某些病毒、单细胞真核生物和后生动物中，尽管不是植物。单体胸腺素、胸腺素重复序列和WH 2结构域的共比对[1]有效地突出了WH 2结构域的保守C末端与胸腺素的六肽基序LKKTET之间的相似性，后者残基长期参与肌动蛋白结合[10，11]。然而，分别比对胸腺素重复序列和WH 2结构域（图1）表明它们的保护模式不是共同延伸的：在胸腺素重复序列中，该基序的C-末端残基有很强的保守性，而WH 2结构域的保守性在N-末端。18-mer WH 2结构域侧翼的C-末端序列是非常异质的，有些到达胸腺素重复序列保守范围内的蛋白质C末端，而在另一些中，相邻的WH 2结构域重叠到该范围内。这两个家庭的肌动蛋白结合模块之间的相似性太低，它们的相关性被检测到相似性搜索。例如，通过比对所有28个已知的串联胸腺素重复序列构建的隐马尔可夫模型[15]，用于搜索非冗余蛋白质，发现单体胸腺素，但没有WH 2结构域。相反，基于WH 2 PFAM种子的HMM [16]，有或没有18个下游残基的增强，都不能检测到胸腺素。LKKTET基序或变体已在与胸腺素或WH 2结构域无关的肌动蛋白结合蛋白中发现，如脊椎动物蛋白激酶C-e（LKKQET）[17]，因此可能已经独立地进化以响应与肌动蛋白结合的共享模式。在凝溶胶蛋白的连接区域中建议的变体FKHVXPN特别令人感兴趣，因为X射线晶体学研究[2]已经揭示了它如何以及在何处与肌动蛋白结合。
In their review ‘‘WH2 domains: a small, versatile adapter for actin monomers’’, Paunola et al.[1] drew attention to sequence similarity between members of two families of actin-binding sequences, WH2 domains and b-thymosins. The authors represented the two as a single family, by extending the original definition of WH2 domains from 18 to 35 residues. From sequence similarity, they inferred common ancestry. The enlarged WH2 domain is gaining currency [2–4], yet evidence for such a relationship is lacking. b-Thymosins are 43 residue peptides with a role in actin dynamics as monomer-sequestering agents [5]. Recently, a number of proteins containing internal tandem repeats of sequences very similar to monomeric b-thymosins have been identified, first in Drosophila and Caenorhabditis [6], more recently in Ciona, Dermacentor and Hermissenda [7]. From studies of the Drosophila protein ciboulot [8], the role of these proteins in regulation of actin filaments is likely to be different from monomeric thymosins. Homologues of b-thymosins have not been identified in single-celled organisms. WH2 domains [9](from Wiskott–Aldrich homology 2) are 18-residue sequences that also confer actin binding, are known only as modular parts of larger proteins, but are widely distributed in phylogeny, being found in bacteria (hypothetical proteins in Rickettsia montana and Vibrio parahaemolyticus), certain viruses of arthropods, single-celled eukaryotes and metazoans, although not plants. Co-alignment of monomeric thymosins, thymosin repeats and WH2 domains [1] usefully highlighted similarity between the conserved C-terminus of WH2 domains and the hexapeptide motif LKKTET of thymosins, the latter residues long implicated in actin binding [10, 11]. However, aligning thymosin repeats and WH2 domains separately (Fig. 1) shows that their patterns of conservation are not co-extensive: there is strong conservation of residues in thymosin repeats C-terminal of this motif, whereas conservation of WH2 domains is N-terminal from it. C-terminal sequences flanking the 18-mer WH2 domains are very heterogeneous, some reach C-terminus of the protein within the conserved span of thymosin repeats, and in others, adjacent WH2 domains overlap into this span. The similarity between these two families of actin binding modules is too low for their relatedness to be detected by similarity searches. For example, a Hidden Markov Model [15] constructed from the alignment of all 28 known tandem thymosin repeats, used to search non-redundant proteins, finds monomeric thymosins, but not WH2 domains. Conversely, an HMM based on the WH2 PFAM seed [16], with or without augmentation by 18 downstream residues, does not detect thymosins.The LKKTET motif, or variants, has been found in actinbinding proteins unrelated to thymosins or WH2 domains, such as vertebrate protein kinases C-e (LKKQET)[17] and so may have evolved independently in response to a shared mode of binding to actin. A suggested variant FKHVXPN in the link region of gelsolin is of particular interest, since an X-ray crystallographic study [2] has revealed how and where this binds to actin.