Frameshift PQBP-1 mutants K192Sfs*7 and R153Sfs*41 implicated in X-linked intellectual disability form stable dimers
Frameshift PQBP-1 mutants K192Sfs*7 and R153Sfs*41 implicated in X-linked intellectual disability form stable dimers
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DOI：
10.1016/j.jsb.2019.04.003
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发表时间：
2019-06-01
影响因子：
3
通讯作者：
Chen, Yu Wai
中科院分区：
文献类型：
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作者：
Rahman, Shah Kamranur;Okazawa, Hitoshi;Chen, Yu Wai
多聚谷氨酰胺片段结合蛋白-1（PQBP-1）是一种核内无序蛋白，在胚胎和胚后发育过程中参与转录调控和RNA剪接。在人类中，它的突变导致严重的认知障碍，称为Renpenning综合征，一种X连锁智力残疾（XLID）。在这里，我们报告了两个PQBP-1移码突变体，K192 S（fS*7）和R153 S（fs*41）的生物物理学研究。两种突变体在溶液中均为二聚体，与单体野生型蛋白相反。这些突变体含有更多的折叠内容物，并具有增加的热稳定性。使用小角度X射线散射数据，我们生成了三维信封，揭示了它们的整体平面形状。我们还描述了每个突变体使用合奏模型的基础上，一个天然样的初始池与二聚体结构的核心。已知PQBP-1通过与RNA聚合酶II的C-末端结构域相互作用来抑制转录，RNA聚合酶II由共有七肽序列YSPTSPS的52个重复组成。我们研究了PQBP-1变体与在位置2和5（YpSPTpSPS）磷酸化的标记肽的结合，发现这种相互作用在两个突变体中显著减弱。
Polyglutamine tract-binding protein-1 (PQBP-1) is a nuclear intrinsically disordered protein playing important roles in transcriptional regulation and RNA splicing during embryonic and postembryonic development. In human, its mutations lead to severe cognitive impairment known as the Renpenning syndrome, a form of X-linked intellectual disability (XLID). Here, we report a combined biophysical study of two PQBP-1 frameshift mutants, K192S(fS*7) and R153S(fs*41). Both mutants are dimeric in solution, in contrast to the monomeric wild-type protein. These mutants contain more folded contents and have increased thermal stabilities. Using small-angle X-ray scattering data, we generated three-dimensional envelopes which revealed their overall flat shapes. We also described each mutant using an ensemble model based on a native-like initial pool with a dimeric structural core. PQBP-1 is known to repress transcription by way of interacting with the C-terminal domain of RNA polymerase II, which consists of 52 repeats of a consensus heptapeptide sequence YSPTSPS. We studied the binding of PQBP-1 variants to the labelled peptide which is phosphorylated at positions 2 and 5 (YpSPTpSPS) and found that this interaction is significantly weakened in the two mutants.