Function of FMRP Domains in Regulating Distinct Roles of Neuronal Protein Synthesis.
|Function of FMRP Domains in Regulating Distinct Roles of Neuronal Protein Synthesis.
|Year of Publication
|D'Souza MNinochka, Ramakrishna S, Radhakrishna BK, Jhaveri V, Ravindran S, Yeramala L, Nair D, Palakodeti D, Muddashetty RS
|Fragile X Mental Retardation Protein, Fragile X Syndrome, Humans, Microtubules, Neurons, Protein Biosynthesis, Ribosomes, RNA, Messenger
The Fragile-X Mental Retardation Protein (FMRP) is an RNA binding protein that regulates translation of mRNAs essential for synaptic development and plasticity. FMRP interacts with a specific set of mRNAs, aids in their microtubule-dependent transport and regulates their translation through its association with ribosomes. However, the biochemical role of FMRP's domains in forming neuronal granules and associating with microtubules and ribosomes is currently undefined. We report that the C-terminus domain of FMRP is sufficient to bind to ribosomes akin to the full-length protein. Furthermore, the C-terminus domain alone is essential and responsible for FMRP-mediated neuronal translation repression. However, dendritic distribution of FMRP and its microtubule association is favored by the synergistic combination of FMRP domains rather than individual domains. Interestingly, we show that the phosphorylation of hFMRP at Serine-500 is important in modulating the dynamics of translation by controlling ribosome association. This is a fundamental mechanism governing the size and number of FMRP puncta that contain actively translating ribosomes. Finally through the use of pathogenic mutations, we emphasize the hierarchical contribution of FMRP's domains in translation regulation.
|DST/INSPIRE Fellowship/2018/IF180201 / / Department of Science and Technology, Ministry of Science and Technology /
DST/SJF/LSA-02/2015-16 / / Department of Science and Technology, Ministry of Science and Technology /
BT/IN/Denmark/07/RSM/2015-2016 / / Department of Biotechnology , Ministry of Science and Technology /
DBT-IISc Partnership program / / Mission on Nano Science and Technology /
IISc-Institute of Eminence (IOE) program / / Indian Institute of Science /