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首页> 外文期刊>Nucleic Acids Research >Homodimerization of RBPMS2 through a new RRM-interaction motif is necessary to control smooth muscle plasticity
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Homodimerization of RBPMS2 through a new RRM-interaction motif is necessary to control smooth muscle plasticity

机译：通过新的RRM相互作用基序使RBPMS2均质化是控制平滑肌可塑性的必要条件

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摘要

In vertebrates, smooth muscle cells (SMCs) can reversibly switch between contractile and proliferative phenotypes. This involves various molecular mechanisms to reactivate developmental signaling pathways and induce cell dedifferentiation. The protein RBPMS2 regulates early development and plasticity of digestive SMCs by inhibiting the bone morphogenetic protein pathway through its interaction with NOGGIN mRNA. RBPMS2 contains only one RNA recognition motif (RRM) while this motif is often repeated in tandem or associated with other functional domains in RRM-containing proteins. Herein, we show using an extensive combination of structure/function analyses that RBPMS2 homodimerizes through a particular sequence motif (D-x-K-x-R-E-L-Y-L-L-F: residues 39-51) located in its RRM domain. We also show that this specific motif is conserved among its homologs and paralogs in vertebrates and in its insect and worm orthologs (CPO and MEC-8, respectively) suggesting a conserved molecular mechanism of action. Inhibition of the dimerization process through targeting a conserved leucine inside of this motif abolishes the capacity of RBPMS2 to interact with the translational elongation eEF2 protein, to upregulate NOG-GIN mRNA in vivo and to drive SMC dedifferentiation. Our study demonstrates that RBPMS2 possesses an RRM domain harboring both RNA-binding and protein-binding properties and that the newly identified RRM-homodimerization motif is crucial for the function of RBPMS2 at the cell and tissue levels.
机译：在脊椎动物中，平滑肌细胞（SMC）可以可逆地在收缩表型和增生表型之间切换。这涉及各种分子机制来重新激活发育信号通路并诱导细胞去分化。 RBPMS2蛋白质通过与NOGGIN mRNA相互作用来抑制骨形态发生蛋白途径，从而调节消化道SMC的早期发育和可塑性。 RBPMS2仅包含一个RNA识别基序（RRM），而该基序通常是串联或与含RRM的蛋白质中的其他功能结构域重复的。本文中，我们显示使用结构/功能分析的广泛组合，RBPMS2通过位于其RRM域中的特定序列基序（D-x-K-x-R-E-L-Y-L-L-F：残基39-51）同源二聚。我们还显示，该特定基序在脊椎动物及其昆虫和蠕虫直系同源物（分别为CPO和MEC-8）中，在其同源物和旁系同源物之间是保守的，提示了作用的保守分子机制。通过靶向该基序内部的保守亮氨酸来抑制二聚化过程，消除了RBPMS2与翻译延伸eEF2蛋白相互作用，在体内上调NOG-GIN mRNA并驱动SMC去分化的能力。我们的研究表明，RBPMS2具有一个既具有RNA结合又具有蛋白质结合特性的RRM结构域，并且新近鉴定出的RRM-同源二聚化基序对于RBPMS2在细胞和组织水平上的功能至关重要。

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