Evolutionary Diversity of Dus2 Enzymes Reveals Novel Structural and Functional Features among Members of the RNA Dihydrouridine Synthases Family.
Evolutionary Diversity of Dus2 Enzymes Reveals Novel Structural and Functional Features among Members of the RNA Dihydrouridine Synthases Family.
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DOI：
10.3390/biom12121760
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发表时间：
2022-11-26
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
二氢尿苷（D）是一种在大多数生物体的tRNA中发现的丰富的修饰碱基，并且最近在真核生物mRNA中被检测到。该碱基赋予RNA分子显著的构象可塑性。二氢尿苷生物合成反应是由一个大家族的黄素酶，二氢尿苷脱氢酶（Dus）催化的。到目前为止，只有细菌Dus酶及其与tRNA的复合物的结构特征。了解真核生物Dus蛋白的结构-功能关系一直受到结构数据缺乏的阻碍。在这里，我们结合了广泛的系统发育分析与高精度的3D分子建模的30多个Dus 2酶选择沿着生命树，以确定这些酶的D生物合成的进化分子基础。Dus 2是负责合成tRNA中的D20的真核酶，并且参与一些人类癌症和阿尔茨海默病中的β-淀粉样肽的解毒。除了形成所有Dus的规范结构的域之外，即，催化TIM桶结构域和螺旋结构域都参与细菌Dus中的RNA识别，大多数Dus 2蛋白在两端都具有延伸。虽然这些主要是N-末端侧的非结构化延伸，但C-末端侧延伸可以采用明确定义的结构，如螺旋和β-折叠，甚至形成额外的结构域，如锌指结构域。还生成了Dus 2/tRNA复合物的3D模型。这项研究表明，真核生物Dus 2蛋白可能具有优势，在tRNA的识别比他们的细菌同行，由于其模块化。
Dihydrouridine (D) is an abundant modified base found in the tRNAs of most living organisms and was recently detected in eukaryotic mRNAs. This base confers significant conformational plasticity to RNA molecules. The dihydrouridine biosynthetic reaction is catalyzed by a large family of flavoenzymes, the dihydrouridine synthases (Dus). So far, only bacterial Dus enzymes and their complexes with tRNAs have been structurally characterized. Understanding the structure-function relationships of eukaryotic Dus proteins has been hampered by the paucity of structural data. Here, we combined extensive phylogenetic analysis with high-precision 3D molecular modeling of more than 30 Dus2 enzymes selected along the tree of life to determine the evolutionary molecular basis of D biosynthesis by these enzymes. Dus2 is the eukaryotic enzyme responsible for the synthesis of D20 in tRNAs and is involved in some human cancers and in the detoxification of β-amyloid peptides in Alzheimer’s disease. In addition to the domains forming the canonical structure of all Dus, i.e., the catalytic TIM-barrel domain and the helical domain, both participating in RNA recognition in the bacterial Dus, a majority of Dus2 proteins harbor extensions at both ends. While these are mainly unstructured extensions on the N-terminal side, the C-terminal side extensions can adopt well-defined structures such as helices and beta-sheets or even form additional domains such as zinc finger domains. 3D models of Dus2/tRNA complexes were also generated. This study suggests that eukaryotic Dus2 proteins may have an advantage in tRNA recognition over their bacterial counterparts due to their modularity.
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影响因子：
14.9
作者：
Blum M;Chang HY;Chuguransky S;Grego T;Kandasaamy S;Mitchell A;Nuka G;Paysan-Lafosse T;Qureshi M;Raj S;Richardson L;Salazar GA;Williams L;Bork P;Bridge A;Gough J;Haft DH;Letunic I;Marchler-Bauer A;Mi H;Natale DA;Necci M;Orengo CA;Pandurangan AP;Rivoire C;Sigrist CJA;Sillitoe I;Thanki N;Thomas PD;Tosatto SCE;Wu CH;Bateman A;Finn RD
通讯作者：
Finn RD
DOI：
10.1107/s0907444910051218
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Bunkóczi G;Read RJ
通讯作者：
Read RJ
影响因子：
14.9
作者：
Bou-Nader, Charles;Barraud, Pierre;Hamdane, Djemel
通讯作者：
Hamdane, Djemel
影响因子：
14.8
作者：
Dai W;Li A;Yu NJ;Nguyen T;Leach RW;Wühr M;Kleiner RE
通讯作者：
Kleiner RE
影响因子：
14.9
作者：
Boccaletto P;Stefaniak F;Ray A;Cappannini A;Mukherjee S;Purta E;Kurkowska M;Shirvanizadeh N;Destefanis E;Groza P;Avşar G;Romitelli A;Pir P;Dassi E;Conticello SG;Aguilo F;Bujnicki JM
通讯作者：
Bujnicki JM