Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1.
Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1.
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DOI：
10.1038/nsmb.1519
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发表时间：
2008-12
影响因子：
16.8
通讯作者：
Patel DJ
中科院分区：
文献类型：
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作者：
Teplova M;Patel DJ
肌肉盲样蛋白(MBNL)是一种发育程序性选择性剪接的调节蛋白，它含有串联CCCH锌指(ZnF)结构域，靶向含有YGCU(U/G)Y序列元件(其中Y是嘧啶)的前mRNAs。在强直性肌营养不良症中，MBNL蛋白水平的降低导致前mRNAs子集的异常选择性剪接。与r(CGCUGU)结合的MBNL1锌F3/4的晶体结构确立了锌F3和锌F4都针对GC步骤，通过主要与蛋白质主链基团形成的氢键网络介导的位点特异性识别。锌氟化锌和锌氟化锌结构域的相对对齐是由结构域间连接子的拓扑决定的，结果是结合的GC元件的反平行取向，支持MBNL1结合的预-mRNA靶标的链逆转环轨迹。我们预计，MBNL1介导的剪接位点附近的环状RNA片段的靶向可能有助于mRNA前的选择性剪接调控。
Muscleblind-like (MBNL) proteins, regulators of developmentally programmed alternative splicing, harbor tandem CCCH zinc-finger (ZnF) domains that target pre-mRNAs containing YGCU(U/G)Y sequence elements (where Y is a pyrimidine). In myotonic dystrophy, reduced levels of MBNL proteins lead to aberrant alternative splicing of a subset of pre-mRNAs. The crystal structure of MBNL1 ZnF3/4 bound to r(CGCUGU) establishes that both ZnF3 and ZnF4 target GC steps, with site-specific recognition mediated by a network of hydrogen bonds formed primarily with main chain groups of the protein. The relative alignment of ZnF3 and ZnF4 domains is dictated by the topology of the interdomain linker, with a resulting antiparallel orientation of bound GC elements, supportive of a chain-reversal loop trajectory for MBNL1-bound pre-mRNA targets. We anticipate that MBNL1-mediated targeting of looped RNA segments proximal to splice-site junctions could contribute to pre-mRNA alternative-splicing regulation.