A Species-Correlated Transitional Residue D132 on Human FMRP Plays a Role in Nuclear Localization via an RNA-Dependent Interaction With PABP1
| Autor: | Yue-Sheng Long, Yong-Ting Zhou, Mei-Mei Gao, Jing-Yi Long, Yong-Hong Yi, Wei-Wen Sun, Yousheng Shu, Hao-Ying Huang, Fei Hu, Jun-Yi Fu, Wei Li |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities RNase P Mutant medicine.disease_cause Poly(A)-Binding Protein I Protein Structure Secondary Protein–protein interaction 03 medical and health sciences Fragile X Mental Retardation Protein Mice 0302 clinical medicine Species Specificity Cell Line Tumor medicine NLS Animals Humans Amino Acid Sequence Cell Nucleus Gene knockdown Mutation Chemistry General Neuroscience RNA nervous system diseases Cell biology 030104 developmental biology HEK293 Cells 030217 neurology & neurosurgery Nuclear localization sequence Protein Binding |
| Zdroj: | Neuroscience. 404 |
| ISSN: | 1873-7544 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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