Characterization of coding synonymous and non-synonymous variants in ADAMTS13 using ex vivo and in silico approaches.
Characterization of coding synonymous and non-synonymous variants in ADAMTS13 using ex vivo and in silico approaches.
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DOI：
10.1371/journal.pone.0038864
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kimchi-Sarfaty C
中科院分区：
文献类型：
--
作者：
Edwards NC;Hing ZA;Perry A;Blaisdell A;Kopelman DB;Fathke R;Plum W;Newell J;Allen CE;S G;Shapiro A;Okunji C;Kosti I;Shomron N;Grigoryan V;Przytycka TM;Sauna ZE;Salari R;Mandel-Gutfreund Y;Komar AA;Kimchi-Sarfaty C
同义变异被定义为不改变编码氨基酸的密码子替换，先前被认为对合成蛋白质的特性没有影响。然而，越来越多的证据表明，这些“沉默”变异可对蛋白质表达和功能产生重大影响，不应再被视为“沉默”。在此，使用多种方法对先前在血管性血友病因子（VWF）裂解止血蛋白酶ADAMTS13基因中发现的6种同义变异和6种非同义变异的影响进行了研究。将ADAMTS13 mRNA和蛋白质表达水平以及变异体的构象和活性与野生型ADAMTS13进行了比较。有趣的是，不仅非同义变异体，同义变异体也被发现会改变蛋白质表达水平、构象和功能。对ADAMTS13 mRNA结构、氨基酸保守性和密码子使用的生物信息学分析使我们能够建立mRNA稳定性、相对同义密码子使用度（RSCU）和细胞内蛋白质表达之间的相关性。这项研究表明，变异体，更具体地说同义变异体，可对ADAMTS13功能产生重大且明确的影响，并且生物信息学分析可能有助于开发预测工具，以识别对编码蛋白质有显著影响的变异体。
Synonymous variations, which are defined as codon substitutions that do not change the encoded amino acid, were previously thought to have no effect on the properties of the synthesized protein(s). However, mounting evidence shows that these “silent” variations can have a significant impact on protein expression and function and should no longer be considered “silent”. Here, the effects of six synonymous and six non-synonymous variations, previously found in the gene of ADAMTS13, the von Willebrand Factor (VWF) cleaving hemostatic protease, have been investigated using a variety of approaches. The ADAMTS13 mRNA and protein expression levels, as well as the conformation and activity of the variants have been compared to that of wild-type ADAMTS13. Interestingly, not only the non-synonymous variants but also the synonymous variants have been found to change the protein expression levels, conformation and function. Bioinformatic analysis of ADAMTS13 mRNA structure, amino acid conservation and codon usage allowed us to establish correlations between mRNA stability, RSCU, and intracellular protein expression. This study demonstrates that variants and more specifically, synonymous variants can have a substantial and definite effect on ADAMTS13 function and that bioinformatic analysis may allow development of predictive tools to identify variants that will have significant effects on the encoded protein.
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作者：
Calcagno AM;Chewning KJ;Wu CP;Ambudkar SV
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影响因子：
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通讯作者：
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