Feb 16, 2019

Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation

Proceedings of the National Academy of Sciences of the United States of America
Brian TsangJulie D Forman-Kay

Abstract

Activity-dependent translation requires the transport of mRNAs within membraneless protein assemblies known as neuronal granules from the cell body toward synaptic regions. Translation of mRNA is inhibited in these granules during transport but quickly activated in response to neuronal stimuli at the synapse. This raises an important question: how does synaptic activity trigger translation of once-silenced mRNAs? Here, we demonstrate a strong connection between phase separation, the process underlying the formation of many different types of cellular granules, and in vitro inhibition of translation. By using the Fragile X Mental Retardation Protein (FMRP), an abundant neuronal granule component and translational repressor, we show that FMRP phase separates in vitro with RNA into liquid droplets mediated by its C-terminal low-complexity disordered region (i.e., FMRPLCR). FMRPLCR posttranslational modifications by phosphorylation and methylation have opposing effects on in vitro translational regulation, which corroborates well with their critical concentrations for phase separation. Our results, combined with bioinformatics evidence, are supportive of phase separation as a general mechanism controlling activity-dependent transla...Continue Reading

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Mentioned in this Paper

Lipid Droplet
Fragile X Syndrome
FMR1
Bio-Informatics
Protein Biosynthesis
Cell Body of Neuron
Terminal (End Postition)
Nucleosome Assembly Protein Gene
RNA, Messenger
Translation Repressor Activity

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