A Species-Correlated Transitional Residue D132 on Human FMRP Plays a Role in Nuclear Localization via an RNA-Dependent Interaction With PABP1
A Species-Correlated Transitional Residue D132 on Human FMRP Plays a Role in Nuclear Localization via an RNA-Dependent Interaction With PABP1
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人类 FMRP 上物种相关的过渡残基 D132 通过与 PABP1 的 RNA 依赖性相互作用在核定位中发挥作用
DOI：
10.1016/j.neuroscience.2019.01.028
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发表时间：
2019-04
期刊：
影响因子：
3.3
通讯作者：
Long Yue-Sheng
中科院分区：
文献类型：
--
作者：
Zhou Yong-Ting;Long Jing-Yi;Fu Jun-Yi;Sun Wei-Wen;Hu Fei;Huang Hao-Ying;Li Wei;Gao Mei-Mei;Shu Yousheng;Yi Yong-Hong;Long Yue-Sheng
脆性X智力低下蛋白（FMRP）是正常脑发育和神经元可塑性的关键决定因素，在mRNA的核质穿梭中起关键作用。然而，参与FMRP核定位的因素仍有待确定。使用跨物种序列比较，我们表明，天冬氨酸在位置132（D132），位于FMRP的保守的核定位信号（NLS），出现在人类和其他哺乳动物，而谷氨酸132（E132）出现在啮齿动物和鸟类。人FMRP-D132 E改变了蛋白质的二级结构并降低了其核定位，而小鼠FMRP-E132 D中的相互取代促进了其核定位。人FMRP可与多聚腺苷酸结合蛋白1（PABP 1）相互作用，但D132 E突变阻碍了这种相互作用。尽管小鼠FMRP不能与PABP 1相互作用，但E132 D突变导致FMRP与PABP 1相互作用。我们进一步表明，人FMRP-D132 E突变体的过表达促进PABP 1在人细胞中的细胞质聚集体的形成，但不促进小鼠FMRP-E132 D在小鼠细胞中的细胞质聚集体的形成。PABP 1敲低减少了人FMRP的核定位，但不是小鼠FMRP。此外，RNA酶A处理降低了使用V5-hFMRP转染的细胞的抗V5免疫沉淀物中的PABP 1水平，表明人FMRP和PABP 1之间以RNA依赖性方式相互作用。因此，我们的数据表明，FMRP蛋白与人类使用的D132容纳一种新的蛋白质-RNA-蛋白质相互作用，这可能涉及FMRP残基转换和神经进化之间的连接。
Fragile X mental retardation protein (FMRP), a key determinant of normal brain development and neuronal plasticity, plays critical roles in nucleocytoplasmic shuttling of mRNAs. However, the factors involved in FMRP nuclear localization remain to be determined. Using cross-species sequence comparison, we show that an aspartate in position 132 (D132), located within the conserved nuclear localization signal (NLS) of FMRP, appears in human and other mammals, while glutamate 132 (E132) appears in rodents and birds. Human FMRP-D132E alters the secondary structure of the protein and reduces its nuclear localization, while the reciprocal substitution in mouse FMRP-E132D promotes its nuclear localization. Human FMRP could interact with poly(A)-binding protein 1 (PABP1) which is impeded by the D132E mutation. Reversely, mouse FMRP could not interact with PABP1, but the E132D mutation leads to the FMRP-PABP1 interaction. We further show that overexpression of human FMRP-D132E mutant promotes the formation of cytoplasmic aggregates of PABP1 in human cells, but not of mouse FMRP-E132D in mouse cells. PABP1 knockdown reduces the nuclear localization of human FMRP, but not mouse FMRP. Furthermore, RNase A treatment decreases the PABP1 levels in the anti-V5-immunoprecipitates using the V5-hFMRP-transfected cells, suggesting an interaction between human FMRP and PABP1 in an RNA-dependent fashion. Thus, our data suggest that the FMRP protein with the human-used D132 accommodates a novel protein-RNA-protein interaction which may implicate a connection between FMRP residue transition and neural evolution.
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影响因子：
16
作者：
Lemieux, Caroline;Marguerat, Samuel;Bachand, Francois
通讯作者：
Bachand, Francois
DOI：
10.1038/nrn4001
发表时间：
2015-10
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Richter JD;Bassell GJ;Klann E
通讯作者：
Klann E
DOI：
10.1038/nsb881
发表时间：
2003-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Süel, GM;Lockless, SW;Ranganathan, R
通讯作者：
Ranganathan, R
影响因子：
11.4
作者：
Fridell, RA;Benson, RE;Cullen, BR
通讯作者：
Cullen, BR
影响因子：
11.4
作者：
Behm-Ansmant, Isabelle;Gatfield, David;Izaurralde, Elisa
通讯作者：
Izaurralde, Elisa