A global view of structure-function relationships in the tautomerase superfamily.
A global view of structure-function relationships in the tautomerase superfamily.
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DOI：
10.1074/jbc.m117.815340
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发表时间：
2018-02-16
期刊：
影响因子：
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通讯作者：
Babbitt PC
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文献类型：
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作者：
Davidson R;Baas BJ;Akiva E;Holliday GL;Polacco BJ;LeVieux JA;Pullara CR;Zhang YJ;Whitman CP;Babbitt PC
互变异构酶超家族（TSF）由整个生物圈中存在的11，000多个非冗余序列组成。由于N-末端脯氨酸的不寻常的和关键的催化作用，特征化的成员引起了人们的广泛关注。这几个特征化的成员催化各种各样的化学反应，但其化学能力和生物功能的全部规模仍然未知。为了获得对TSF结构-功能关系的新见解，我们对整个超家族的相似性进行了全局分析，并计算了一个序列相似性网络，以指导将其分类为不同的亚组。我们的研究结果表明，TSF成员被发现在所有领域的生活，与大多数存在于细菌。顺式-3-氯丙烯酸脱卤酶亚组的真核成员仅限于真菌物种，而巨噬细胞迁移抑制因子亚组具有广泛的真核代表性（包括哺乳动物）。出乎意料的是，我们发现346个TSF序列缺乏Pro-1，其中85%存在于丙二酸半醛脱羧酶亚组中。计算网络还能够识别相似性路径，即连接功能不同的亚组并表现出过渡结构特征的序列，这些特征可能有助于解释反应分歧。这些接头蛋白的结构指导的比较确定了它们之间的保守转换，和动力学分析证实了这些意见。系统发育重建的链接集是与这些发现相一致的。我们的研究结果还表明，当代TSF成员可能是从一个短的4-α-巴豆酸互变异构酶样的祖先，然后基因复制和融合。我们的新的接头引导的策略可以用来丰富其他酶超家族的序列/结构/功能转换的发现。
The tautomerase superfamily (TSF) consists of more than 11,000 nonredundant sequences present throughout the biosphere. Characterized members have attracted much attention because of the unusual and key catalytic role of an N-terminal proline. These few characterized members catalyze a diverse range of chemical reactions, but the full scale of their chemical capabilities and biological functions remains unknown. To gain new insight into TSF structure–function relationships, we performed a global analysis of similarities across the entire superfamily and computed a sequence similarity network to guide classification into distinct subgroups. Our results indicate that TSF members are found in all domains of life, with most being present in bacteria. The eukaryotic members of the cis-3-chloroacrylic acid dehalogenase subgroup are limited to fungal species, whereas the macrophage migration inhibitory factor subgroup has wide eukaryotic representation (including mammals). Unexpectedly, we found that 346 TSF sequences lack Pro-1, of which 85% are present in the malonate semialdehyde decarboxylase subgroup. The computed network also enabled the identification of similarity paths, namely sequences that link functionally diverse subgroups and exhibit transitional structural features that may help explain reaction divergence. A structure-guided comparison of these linker proteins identified conserved transitions between them, and kinetic analysis paralleled these observations. Phylogenetic reconstruction of the linker set was consistent with these findings. Our results also suggest that contemporary TSF members may have evolved from a short 4-oxalocrotonate tautomerase–like ancestor followed by gene duplication and fusion. Our new linker-guided strategy can be used to enrich the discovery of sequence/structure/function transitions in other enzyme superfamilies.