A new regulatory function of the region proximal to the RGG box in the Fragile X mental retardation protein

Blackwell, Ernest; Ceman, Stephanie

doi:10.1242/jcs.086751

Cited by 15 publications

(16 citation statements)

References 39 publications

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“…One possibility is that in the activated synapse, FMRP is polyubiquitinated and rapidly degraded by the proteasome to relieve the translational inhibition (Hou et al, 2006; Nalavadi et al, 2012). Another possibility is that post-translational modification of FMRP (phosphorylation or methylation) will modulate its affinity for the ribosome (Blackwell and Ceman, 2011; Ceman et al, 2003; Denman, 2002; Dolzhanskaya et al, 2006; Siomi et al, 2002). More studies are needed to understand how the interaction of FMRP with the ribosome is modulated by sequences or structures in the mRNA and by modifications to FMRP.…”

Section: Mechanism Of Translational Repression By Fmrpmentioning

confidence: 99%

Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins

Chen

Joseph

2015

Biochimie

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Translational control is a common mechanism used to regulate gene expression and occur in bacteria to mammals. Typically in translational control, an RNA-binding protein binds to a unique sequence in the mRNA to regulate protein synthesis by the ribosomes. Alternatively, a protein may bind to or modify a translation factor to globally regulate protein synthesis by the cell. Here, we review translational control by the fragile X mental retardation protein (FMRP), the absence of which causes the neurological disease, fragile X syndrome (FXS).

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Section: Mechanism Of Translational Repression By Fmrpmentioning

confidence: 99%

Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins

Chen

Joseph

2015

Biochimie

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“…In its unmethylated form, FMRP binds RNAs containing a G‐quadruplex structure (sc1‐like RNA, black). Upon activation, PRMT1 (yellow) methylates FMRP, rendering it unable to bind G‐quadruplex‐containing structures, but is still able to bind other RNAs such as AATYK (green; Blackwell and Ceman, 2011), which participate in neurite outgrowth (Tomomura et al, 2007). PRMT1 is modulated by the cell cycle (Kim et al, 2010), and is required for neurite outgrowth (Miyata et al, 2008).…”

Section: Role Of Arginine Methylation Of Rna‐binding Proteins In Neurmentioning

confidence: 99%

“…Although the sites of methylation for FMRP have been identified (Stetler et al, 2006) and PRMT1 has been identified as a PRMT capable of methylating the protein in cells (Blackwell et al, 2010), additional PRMTs have been shown to methylate FMRP in vitro (Dolzhanskaya et al, 2006) and might also be capable of methylating one or more sites within FMRP in vivo. Methylation of FMRP has been shown to affect RNA association (Blackwell et al, 2010), and the RGG box is required for association with the RNA‐binding protein Yb1/p50 (Blackwell and Ceman, 2011), suggesting that methylation may also affect protein interactions. It is possible that methylation of FMRP affects binding of both RNAs and protein or, alternatively, that only RNA binding is affected and RNA binding is a prerequisite for protein binding (or vice versa).…”

Section: Perspectivementioning

confidence: 99%

Arginine methylation of RNA‐binding proteins regulates cell function and differentiation

Blackwell

Ceman

2012

Molecular Reproduction Devel

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Arginine methylation is a post-translational modification that regulates protein function. RNA-binding proteins are an important class of cell function mediators, some of which are methylated on arginine. Early studies of RNA-binding proteins and arginine methylation are briefly introduced, and the enzymes that mediate this post-translational modification are described. We review the most common RNA-binding domains and briefly discuss how they associate with RNAs. We address the following groups of RNA-binding proteins: hnRNP, Sm, Piwi, Vasa, FMRP, and HuD. hnRNPs were the first RNA-binding proteins found to be methylated on arginine. The Sm proteins function in RNA processing and germ cell specification. The Piwi proteins are largely germ cell specific that are also required for germ cell production, as is Vasa. FMRP participates in germ cell formation in Drosophila but is more widely known for its neuronal function. Similarly, HuD plays a role in nervous system development and function. We review the effects of arginine methylation on the function of each protein, then conclude by addressing remaining questions and future directions of arginine methylation as an important and emerging area of regulation.

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“…Notably, binding of FMRP to G-rich RNAs in vitro requires only the RGG motif, which specifically interacts with natural and in vitro selected G-quadruplex-containing RNAs such as a 35-nucleotide sc1 RNA (21,(26)(27)(28)(29). Recent studies showed that G-quadruplexes facilitate mRNA interactions with ribosome-bound FMRP (30), whereas the RGG motif, in addition to mRNA binding, contributes to association with ribosomes and proteins and translational control (14,(31)(32)(33)(34). The RGG motif is well conserved in FMRP of vertebrates but differs significantly from…”

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confidence: 99%

Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP

Vasilyev

Polonskaia

Darnell

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

180

181

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Fragile X Mental Retardation Protein (FMRP) is a regulatory RNA binding protein that plays a central role in the development of several human disorders including Fragile X Syndrome (FXS) and autism. FMRP uses an arginine-glycine-rich (RGG) motif for specific interactions with guanine (G)-quadruplexes, mRNA elements implicated in the disease-associated regulation of specific mRNAs. Here we report the 2.8-Å crystal structure of the complex between the human FMRP RGG peptide bound to the in vitro selected G-rich RNA. In this model system, the RNA adopts an intramolecular K + -stabilized G-quadruplex structure composed of three G-quartets and a mixed tetrad connected to an RNA duplex. The RGG peptide specifically binds to the duplex-quadruplex junction, the mixed tetrad, and the duplex region of the RNA through shape complementarity, cation-π interactions, and multiple hydrogen bonds. Many of these interactions critically depend on a type I β-turn, a secondary structure element whose formation was not previously recognized in the RGG motif of FMRP. RNA mutagenesis and footprinting experiments indicate that interactions of the peptide with the duplex-quadruplex junction and the duplex of RNA are equally important for affinity and specificity of the RGG-RNA complex formation. These results suggest that specific binding of cellular RNAs by FMRP may involve hydrogen bonding with RNA duplexes and that RNA duplex recognition can be a characteristic RNA binding feature for RGG motifs in other proteins.R NA-binding proteins (RBPs) control all aspects of RNA metabolism and are fundamental to core cellular processes. ∼14% of identified human RBPs are implicated in a broad spectrum of human pathologies, including neurodegenerative and muscular diseases, metabolic disorders, and cancers (1, 2). Fragile X Mental Retardation Protein (FMRP) is among the most important RBPs because of its central role in several human diseases (3). Loss of FMRP function due to CGG triplet repeat expansion-associated transcriptional silencing or missense mutations in the protein (4, 5) lead to fragile X syndrome (FXS), the most common cause of inherited intellectual disability. Mutations in FMRP are also the leading monogenic cause of autism (6, 7). Intermediate length repeat expansions in the FMR1 gene are linked to fragile X-associated tremor ataxia syndrome (8) and fragile X-associated primary ovarian insufficiency (9).FMRP contains four canonical nucleic acid-binding motifs, three KH domains and one arginine-glycine-rich (RGG) box, which mediate interactions with RNAs in mRNA transport, storage, stability, and regulation of translation (Fig. 1A) (3, 10). Each KH domain has been reported to have a mutation either causing FXS or found in patients with intellectual disability (4, 5, 11). In neurons, FMRP associates with a subset of mRNAs and represses their translation both in the cell body and near synapses (12). Loss of repression of these mRNAs is associated with alterations in synaptic plasticity and dendritic spine dynamics thought to underlie...

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A new regulatory function of the region proximal to the RGG box in the Fragile X mental retardation protein

Cited by 15 publications

References 39 publications

Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins

Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins

Arginine methylation of RNA‐binding proteins regulates cell function and differentiation

Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP

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