Structural and functional implications of positive selection at the primate angiogenin gene.
Structural and functional implications of positive selection at the primate angiogenin gene.
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DOI：
10.1186/1471-2148-7-167
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发表时间：
2007-09-20
影响因子：
3.4
通讯作者：
Ramos MJ
中科院分区：
文献类型：
--
作者：
Osorio DS;Antunes A;Ramos MJ
血管生成（新血管的形成）是发育中的原始过程，其失调在许多疾病的发病机制中起着核心作用。血管生成素 (ANG) 是 RNase A 超家族的一个特殊成员，是一种有效的血管生成诱导剂，涉及许多不同类型的癌症、肌萎缩侧索硬化症，并且可能在先天免疫防御中发挥作用。这个家族的进化道路是一条高度动态的道路，其中正选择发挥了重要作用。在这项工作中，我们使用基因和蛋白质水平相结合的方法来确定灵长类ANG基因多样化选择下的主要位点，并分析其结构和功能含义。我们获得了灵长类 ANG 基因正向选择的证据。位点特异性分析指出有 15 个位点处于正选择状态，其中大多数也表现出氨基酸特性的剧烈变化。 ANG 3D 结构中这些位点的映射描述了五个簇，其中四个位于功能区域：两个位于活性位点区域，一个位于核仁定位信号，一个位于细胞结合位点。灵长类 ANG 基因中选择的 15 个位点中有 8 个在 RNase A 家族中高度或中度保守，表明这是一个定向事件，而不是局部结构或功能许可的简单结果。此外，11 个位点暴露于蛋白质表面，表明它们可能影响 ANG 进行的相互作用。使用最大似然基因水平分析，我们确定了灵长类 ANG 基因中正选择的 15 个位点，并通过氨基酸特性的根本变化的蛋白质水平分析进一步证实了这些位点。这些位点映射到 ANG 蛋白的主要功能区域。事实上，血管生成所需的所有 ANG 区域都存在正选择的证据，这一事实可能很好地表明血管生成是选择过程。然而，需要考虑的其他可能性来自于 ANG 可能参与先天免疫以及与其相互作用的蛋白质和配体的潜在影响或共同进化。
Angiogenesis, the formation of new blood vessels, is a primordial process in development and its dysregulation has a central role in the pathogenesis of many diseases. Angiogenin (ANG), a peculiar member of the RNase A superfamily, is a potent inducer of angiogenesis involved in many different types of cancer, amyotrophic lateral sclerosis and also with a possible role in the innate immune defense. The evolutionary path of this family has been a highly dynamic one, where positive selection has played a strong role. In this work we used a combined gene and protein level approach to determine the main sites under diversifying selection on the primate ANG gene and analyze its structural and functional implications. We obtained evidence for positive selection in the primate ANG gene. Site specific analysis pointed out 15 sites under positive selection, most of which also exhibited drastic changes in amino acid properties. The mapping of these sites in the ANG 3D-structure described five clusters, four of which were located in functional regions: two in the active site region, one in the nucleolar location signal and one in the cell-binding site. Eight of the 15 sites under selection in the primate ANG gene were highly or moderately conserved in the RNase A family, suggesting a directed event and not a simple consequence of local structural or functional permissiveness. Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG. Using a maximum likelihood gene level analysis we identified 15 sites under positive selection in the primate ANG genes, that were further corroborated through a protein level analysis of radical changes in amino acid properties. These sites mapped onto the main functional regions of the ANG protein. The fact that evidence for positive selection is present in all ANG regions required for angiogenesis may be a good indication that angiogenesis is the process under selection. However, other possibilities to be considered arise from the possible involvement of ANG in innate immunity and the potential influence or co-evolution with its interacting proteins and ligands.
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DOI：
10.1073/pnas.94.6.2204
发表时间：
1997-03-18
影响因子：
11.1
作者：
Hu, GF;Riordan, JF;Vallee, BL
通讯作者：
Vallee, BL
影响因子：
2.9
作者：
FETT, JW;STRYDOM, DJ;VALLEE, BL
通讯作者：
VALLEE, BL
影响因子：
4.4
作者：
Cho, S;Beintema, JJ;Zhang, JZ
通讯作者：
Zhang, JZ
影响因子：
30.8
作者：
Greenway, MJ;Andersen, PM;Hardiman, O
通讯作者：
Hardiman, O
影响因子：
3.5
作者：
da Fonseca, Rute R.;Antunes, Agostinho;Ramos, Maria Joao
通讯作者：
Ramos, Maria Joao