Evolutionary analysis of selective constraints identifies ameloblastin (AMBN) as a potential candidate for amelogenesis imperfecta.
Evolutionary analysis of selective constraints identifies ameloblastin (AMBN) as a potential candidate for amelogenesis imperfecta.
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DOI：
10.1186/s12862-015-0431-0
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发表时间：
2015-07-30
影响因子：
3.4
通讯作者：
Sire JY
中科院分区：
文献类型：
--
作者：
Delsuc F;Gasse B;Sire JY
成釉蛋白(ameloblastin，AMBN)是一种在釉质形成过程中分泌的富含脯氨酸/谷氨酰胺的磷酸化蛋白质。以前的研究表明，这种釉质基质蛋白在脊椎动物进化的早期就存在，并在釉质形成过程中发挥着重要作用，尽管它的确切功能尚不清楚。我们进行AMBN的进化分析是为了(I)确定对蛋白质功能重要的残基和基序，(Ii)预测导致遗传病的突变，以及(Iii)了解其在哺乳动物中的分子进化。在电子计算机搜索中，检索了公共数据库中的56个完整序列，并对其进行了比对和计算分析。我们发现，AMBN在哺乳动物的适度纯化选择下是全球进化的，并且包含着强烈的系统发育信号。此外，我们的分析显示，密码子在显著的正向选择下进化。在卡他灵长类动物和斑腿猴身上观察到了作用于AMBN的正向选择的证据。我们还发现：(I)在祖先胎盘AMBN中招募了一个额外的翻译起始点，(Ii)在包括卡他灵长类在内的各种物种中多次复制了一个短外显子，以及(Iii)存在几个多聚腺苷酸化位点。AMBN拥有多个职位，2亿年来一直承受着强大的选择压力。这些位置对应于几个裂解位点和羟化、O-糖基化和磷酸化残基。我们预测，如果被替换，这些保守的位置可能会导致釉质紊乱。一些以前被确定为潜在重要功能的基序得到了确认，我们发现了两个高度保守的新基序，其功能应该在不久的将来进行测试。这项研究说明了进化分析的力量，以表征作用于尚未表征结构的蛋白质的功能约束。本文的在线版本(doi：10.1186/s12862-0150431-0)包含补充材料，授权用户可以使用。
Ameloblastin (AMBN) is a phosphorylated, proline/glutamine-rich protein secreted during enamel formation. Previous studies have revealed that this enamel matrix protein was present early in vertebrate evolution and certainly plays important roles during enamel formation although its precise functions remain unclear. We performed evolutionary analyses of AMBN in order to (i) identify residues and motifs important for the protein function, (ii) predict mutations responsible for genetic diseases, and (iii) understand its molecular evolution in mammals. In silico searches retrieved 56 complete sequences in public databases that were aligned and analyzed computationally. We showed that AMBN is globally evolving under moderate purifying selection in mammals and contains a strong phylogenetic signal. In addition, our analyses revealed codons evolving under significant positive selection. Evidence for positive selection acting on AMBN was observed in catarrhine primates and the aye-aye. We also found that (i) an additional translation initiation site was recruited in the ancestral placental AMBN, (ii) a short exon was duplicated several times in various species including catarrhine primates, and (iii) several polyadenylation sites are present. AMBN possesses many positions, which have been subjected to strong selective pressure for 200 million years. These positions correspond to several cleavage sites and hydroxylated, O-glycosylated, and phosphorylated residues. We predict that these conserved positions would be potentially responsible for enamel disorder if substituted. Some motifs that were previously identified as potentially important functionally were confirmed, and we found two, highly conserved, new motifs, the function of which should be tested in the near future. This study illustrates the power of evolutionary analyses for characterizing the functional constraints acting on proteins with yet uncharacterized structure. The online version of this article (doi:10.1186/s12862-015-0431-0) contains supplementary material, which is available to authorized users.