The Human Fragile X Mental Retardation Protein Inhibits the Elongation Step of Translation through Its RGG and C-Terminal Domains

Athar, Youssi Momen; Joseph, Simpson

doi:10.1021/acs.biochem.0c00534

Cited by 15 publications

(37 citation statements)

References 60 publications

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“…9c ). Confirming previous reports 40 , 41 , a switch-like translation inhibition response that parallels phase separation is observed increasing the concentration of the RGG construct (Fig. 9b, c ).…”

Section: Resultssupporting

confidence: 92%

Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

et al. 2021

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Specialised ribonucleoprotein (RNP) granules are a hallmark of polarized cells, like neurons and germ cells. Among their main functions is the spatial and temporal modulation of the activity of specific mRNA transcripts that allow specification of primary embryonic axes. While RNPs composition and role are well established, their regulation is poorly defined. Here, we demonstrate that Hecw, a newly identified Drosophila ubiquitin ligase, is a key modulator of RNPs in oogenesis and neurons. Hecw depletion leads to the formation of enlarged granules that transition from a liquid to a gel-like state. Loss of Hecw activity results in defective oogenesis, premature aging and climbing defects associated with neuronal loss. At the molecular level, reduced ubiquitination of the Fmrp impairs its translational repressor activity, resulting in altered Orb expression in nurse cells and Profilin in neurons.

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Section: Resultssupporting

confidence: 92%

Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

et al. 2021

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“…Our results describe an overall inhibition of protein synthesis in neurons expressing full-length FMRP. Independent studies separately claim that the KH and C-terminus domains are involved in this FMRP-mediated translation inhibition (24,37) but our experimental observations support the C-terminus in translational inhibition, analogous to the full-length FMRP ( Fig 7B ).…”

Section: Discussionmentioning

confidence: 42%

Section: Discussionmentioning

confidence: 99%

“…It also directed our attention to determine which of the domains of FMRP are implicated in this process. Previously it was shown that hFMRP inhibits translation through direct binding of the C-terminus RGG domain to the ribosome (24). Likewise, our in-vitro binding assays indicate that the C-terminus domain alone can directly bind to the 80S ribosome while the N-terminus and KH domains cannot ( Fig.7A ).…”

Section: Discussionmentioning

confidence: 99%

“…Only a few studies address the mechanism of these interactions through truncations and mutations of FMRP. The N-terminus domain of FMRP is shown to modulate the expression and activity of several ion channels (22,23) while the RGG domain in the C-terminus is implicated in RNA binding and consequent gene expression (24,25). Further, the I304N mutation of FMRP, which results in a severe form of FXS, illustrates the importance of KH domains in polysome association and translation regulation (16,26).…”

Section: Introductionmentioning

confidence: 99%

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Function of FMRP domains in regulating distinct roles of neuronal protein synthesis

D’Souza

Ramakrishna

Radhakrishna

et al. 2021

Preprint

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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 and aids in their microtubule dependent transport and regulates their translation through its association with ribosomes. However, the biochemical role of individual domains of FMRP in forming neuronal granules and associating with microtubules and ribosomes is currently undefined. Here, we report that the C-terminus domain of FMRP is sufficient to bind to ribosomes as well as polysomes akin to the full-length protein. Furthermore, the C-terminus domain alone is essential and responsible for FMRP-mediated translation repression in neurons. However, FMRP-mediated puncta formation and microtubule association is favored by the synergistic combination of FMRP domains and not by individual domains. Interestingly, we show that the phosphorylation of hFMRP at Serine-500 is important in modulating the dynamics of translation by controlling ribosome/polysome association. This is a fundamental mechanism governing the size and number of FMRP puncta, which appear to contain actively translating ribosomes. Finally through the use of pathogenic mutations, we emphasize the hierarchy of the domains of FMRP in their contribution to translation regulation.

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The RGG motif proteins: Interactions, functions, and regulations

Chowdhury

Jin

2022

WIREs RNA

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Proteins with motifs rich in arginines and glycines were discovered decades ago and are functionally involved in a staggering range of essential processes in the cell. Versatile, specific, yet adaptable molecular interactions enabled by the unique combination of arginine and glycine, combined with multiplicity of molecular recognition conferred by repeated di-, tri-, and multiple peptide motifs, allow RGG motif proteins to interact with a broad range of proteins and nucleic acids. Furthermore, posttranslational modifications at the arginines in the motif extend the RGG protein's capacity for a fine-tuned regulation. In this review, we focus on the biochemical properties of the RGG motif, its molecular interactions with RNAs and proteins, and roles of the posttranslational modification in modulating their interactions. We discuss current knowledge of the RGG motif proteins involved in mRNA transport and translation, highlight our merging understanding of their molecular functions in translational regulation and summarize areas of research in the future critical in understanding this important family of proteins.

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The Human Fragile X Mental Retardation Protein Inhibits the Elongation Step of Translation through Its RGG and C-Terminal Domains

Cited by 15 publications

References 60 publications

Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

Hecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles

Function of FMRP domains in regulating distinct roles of neuronal protein synthesis

The RGG motif proteins: Interactions, functions, and regulations

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