Thermodynamics of the fragile X mental retardation protein RGG box interactions with G quartet forming RNA.
Thermodynamics of the fragile X mental retardation protein RGG box interactions with G quartet forming RNA.
复制标题
脆弱的 X 智力低下蛋白 RGG 盒与形成 RNA 的 G 四联体相互作用的热力学。
DOI：
10.1021/bi060209a
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Mihailescu,Mihaela-Rita
中科院分区：
文献类型：
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作者：
Zanotti,KimberlyJ;Lackey,PatrickE;Evans,GenevieveL;Mihailescu,Mihaela-Rita
脆性X综合征是遗传性智力低下的最常见形式，是脆性X智力低下-1（FMR 1）基因的5' UTR中CGG三核苷酸重复不稳定扩增的结果。CGG重复序列的异常甲基化导致FMR 1基因的转录沉默，从而导致脆性X智力低下蛋白（FMRP）的缺失。FMRP是一种RNA结合蛋白，其使用其RGG盒基序与G四联体形成RNA结合。在这项研究中，我们进行了热力学分析的FMRP RGG框域和Sc 1之间的相互作用，这是一种RNA分子，以前已被证明是结合具有高亲和力的全长FMRP和其RGG框域。我们已经确定，FMRP RGG盒和Sc 1 RNA之间的关联主要是由疏水和氢键相互作用，与静电相互作用的微小贡献，并且FMRP RGG盒结合显著增加了G四联体RNA结构的稳定性。有趣的是，我们发现G四联体识别对于FMRP RGG盒与该RNA靶点的结合是必要的，但不是充分的，这表明肽可能与茎和/或茎-G四联体连接区的额外相互作用是必需的。我们的研究结果还表明，G四联体RNA识别不是RGG盒基序的一般特征，而是携带一些序列，蛋白质和/或RNA，特异性。
Fragile X syndrome, the most common form of inherited mental retardation, is the result of an unstable expansion of a CGG trinucleotide repeat in the 5‘ UTR of the fragile X mental retardation-1 (FMR1) gene. The abnormal hypermethylation of the expanded CGG repeats causes the transcriptional silencing of theFMR1gene and, consequently, the loss of the fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that binds to G quartet forming RNA using its RGG box motif. In this study we have performed a thermodynamic analysis of the interactions between the FMRP RGG box domain and Sc1, an RNA molecule which had been previously shown to be bound with high affinity by both the full-length FMRP and by its RGG box domain. We have determined that the association between the FMRP RGG box and Sc1 RNA is dominated by hydrophobic and hydrogen bond interactions, with minor contributions from electrostatic interactions, and that the FMRP RGG box binding increases the stability of the G quartet RNA structure significantly. Interestingly, we found that the G quartet recognition is necessary but not sufficient for the FMRP RGG box binding to this RNA target, indicating that additional interactions of the peptide, possibly with the stem and/or stem−G quartet junction region, are required. Our results also indicate that the G quartet RNA recognition is not a general feature of the RGG box motif but rather carries some sequence, protein and/or RNA, specificity.