IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties
IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties
复制标题
DOI：
10.1093/nar/gkz136
复制
发表时间：
2019-05-07
影响因子：
14.9
通讯作者：
Ramos, Andres
中科院分区：
文献类型：
--
作者：
Dagil, Robert;Ball, Neil J.;Ramos, Andres
胰岛素样生长因子2(IGF2)mRNA结合蛋白1(IMP1)是机体发育过程中信使RNA(MRNA)代谢和运输的关键调节因子，在癌症中，其错误调控是肿瘤转移的重要组成部分。IMP1的功能依赖于多个RNA结合域的组合作用所介导的一组不同的mRNA靶点的识别。在这里，我们剖析了IMP1的两个关键RNA结合域Kh1和Kh2的结构和RNA结合特性，并建立了识别RNA靶标的动力学模型。我们的数据和模型解释了这两个结构域是如何组织成分子间的伪二聚体的，并且它们在mRNA靶标识别中发挥的重要作用是由KH1KH2-RNA识别单元的高RNA结合亲和力和快速动力学所支持的。重要的是，KH1KH2与RNA的高亲和力结合是通过结构域间耦合实现的，比蛋白质中第二个伪二聚体KH3KH4的作用强50倍。这种强耦合的存在支持了RNA重新建模在IMP1识别已知癌症靶点中的作用。
IGF2 mRNA-binding protein 1 (IMP1) is a key regulator of messenger RNA (mRNA) metabolism and transport in organismal development and, in cancer, its mis-regulation is an important component of tumour metastasis. IMP1 function relies on the recognition of a diverse set of mRNA targets that is mediated by the combinatorial action of multiple RNA-binding domains. Here, we dissect the structure and RNA-binding properties of two key RNA-binding domains of IMP1, KH1 and KH2, and we build a kinetic model for the recognition of RNA targets. Our data and model explain how the two domains are organized as an intermolecular pseudo-dimer and that the important role they play in mRNA target recognition is underpinned by the high RNA-binding affinity and fast kinetics of this KH1KH2-RNA recognition unit. Importantly, the high-affinity RNA-binding by KH1KH2 is achieved by an inter-domain coupling 50-fold stronger than that existing in a second pseudodimer in the protein, KH3KH4. The presence of this strong coupling supports a role of RNA re-modelling in IMP1 recognition of known cancer targets.