Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes
Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes
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DOI：
10.1101/gad.1276805
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发表时间：
2005-04-15
影响因子：
10.5
通讯作者：
Darnell, RB
中科院分区：
文献类型：
--
作者：
Darnell, JC;Fraser, CE;Darnell, RB
脆性X智力低下是由编码脆性X智力低下蛋白FMRP的单个基因的功能丧失引起的，FMRP是一种RNA结合蛋白，具有两个KH型和一个RGG型RNA结合结构域。先前的研究确定了分子内G-四联体RNA作为RGG盒的高亲和力靶点，但RNA结合FMRP功能和智力低下的关系仍不清楚。一个严重受影响的患者在第二个KH结构域（KH 2）内存在错义突变（I304 N），一些证据表明该结构域可能参与FMRP在翻译调控中的拟议作用。我们现在确定的RNA目标的KH 2结构域作为一个复杂的三级结构内的序列特异性元件称为FMRP接吻复合物。我们证明，该协会的FMRP与脑多聚核糖体被废除的竞争与FMRP接吻复杂的RNA，但不是由高亲和力的G-四联体RNA。我们的结论是，与1304 N突变相关的精神发育迟滞，更普遍的可能是脆性X综合征，可能与携带接吻复合体基序的RNA作为FMRP翻译调控靶点的关键作用有关。
Fragile-X mental retardation is caused by loss of function of a single gene encoding the Fragile-X mental retardation protein, FMRP, an RNA-binding protein that harbors two KH-type and one RGG-type RNA-binding domains. Previous studies identified intramolecular G-quartet RNAs as high-affinity targets for the RGG box, but the relationship of RNA binding to FMRP function and mental retardation remains unclear. One severely affected patient harbors a missense mutation (I304N) within the second KH domain (KH2), and some evidence suggests this domain may be involved in the proposed role of FMRP in translational regulation. We now identify the RNA target for the KH2 domain as a sequence-specific element within a complex tertiary structure termed the FMRP kissing complex. We demonstrate that the association of FMRP with brain polyribosomes is abrogated by competition with the FMRP kissing complex RNA, but not by high-affinity G-quartet RNAs. We conclude that mental retardation associated with the 1304N mutation, and likely the Fragile-X syndrome more generally, may relate to a crucial role for RNAs harboring the kissing complex motif as targets for FMRP translational regulation.