scholarly journals Molecular dynamics of FMRP and other RNA-binding proteins in MEG-01 differentiation: the role of mRNP complexes in non-neuronal development

2016 ◽  
Vol 94 (6) ◽  
pp. 597-608 ◽  
Author(s):  
M. McCoy ◽  
D. Poliquin-Duchesneau ◽  
F. Corbin
Keyword(s):  
Protein Content ◽  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Morphological Changes ◽  
Fragile X ◽  
Cellular Protein ◽  
The Body ◽  
Total Protein Content

Asymmetrically differentiating cells are formed with the aid of RNA-binding proteins (RBPs), which can bind, stabilize, regulate, and transport target mRNAs. The loss of RBPs in neurons may lead to severe neurodevelopmental diseases such as the Fragile X Syndrome with the absence of the Fragile X Mental Retardation Protein (FMRP). Because the latter is ubiquitous and shares many similarities with other RBPs involved in the development of peripheral cells, we suggest that FMRP would have a role in the differentiation of all tissues where it is expressed. A MEG-01 differentiation model was, therefore, established to study the global developmental functions of FMRP. PMA induction of MEG-01 cells causes important morphological changes driven by cytoskeletal dynamics. Cytoskeleton change and colocalization analyses were performed by confocal microscopy and sucrose gradient fractionation. Total cellular protein content and de novo synthesis were also analyzed. Microtubular transport mediates the displacement of FMRP and other RBP-containing mRNP complexes towards regions of the cell in development. De novo protein synthesis decreases significantly upon differentiation and total protein content composition is altered. Because those results are comparable with those obtained in neurons, the absence of FMRP would have significant consequences in cells everywhere in the body. The latter should be further investigated to give a better understanding of the systemic implications of imbalances of FMRP and other functionally similar RBPs.

RNA-Binding Proteins and Translation in Neurodegenerative Disease

2020 ◽  
Author(s):  
Kent E. Duncan
Keyword(s):  
Neurodegenerative Diseases ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Potential Contribution ◽  
Fused In Sarcoma ◽  
Specific Mrnas ◽  
Ataxia Syndrome ◽  
Research Frontiers

Both RNA-binding proteins (RBPs) and translation are increasingly implicated in several neurodegenerative diseases, but their specific roles in promoting disease are not yet fully defined. This chapter critically evaluates the evidence that altered translation of specific mRNAs mediated by RNA-binding proteins plays an important role in driving specific neurodegenerative diseases. First, diseases are discussed where a causal role for RNA-binding proteins in disease appears solid, but whether this involves altered translation is less clear. The main foci here are TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Subsequently, diseases are presented where altered translation is believed to contribute, but involvement of RNA-binding proteins is less clear. These include Huntington’s and other repeat expansion disorders such as fragile X tremor/ataxia syndrome (FXTAS), where repeat-induced non-AUG-initiated (RAN) translation is a focus. The potential contribution of both canonical and non-canonical RBPs to altered translation in Parkinson’s disease is discussed. The chapter closes by proposing key research frontiers for the field to explore and outlining methodological advances that could help to address them.

scholarly journals De-novo protein function prediction using DNA binding and RNA binding proteins as a test case

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Sapir Peled ◽  
Olga Leiderman ◽  
Rotem Charar ◽  
Gilat Efroni ◽  
Yaron Shav-Tal ◽  
...  
Keyword(s):  
Dna Binding ◽  
Protein Function ◽  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Protein Function Prediction ◽  
Function Prediction ◽  
Test Case

scholarly journals De novo design of RNA-binding proteins with a prion-like domain related to ALS/FTD proteinopathies

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Kana Mitsuhashi ◽  
Daisuke Ito ◽  
Kyoko Mashima ◽  
Munenori Oyama ◽  
Shinichi Takahashi ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
De Novo Design

scholarly journals Axonal localization of the fragile X family of RNA binding proteins is conserved across mammals

2019 ◽  
Vol 528 (3) ◽  
pp. 502-519 ◽  
Author(s):  
Katherine A. Shepard ◽  
Lulu I T. Korsak ◽  
Danielle DeBartolo ◽  
Michael R. Akins
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X

scholarly journals FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Raeann Goering ◽  
Laura I Hudish ◽  
Bryan B Guzman ◽  
Nisha Raj ◽  
Gary J Bassell ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Rna Localization ◽  
Null Mouse ◽  
Rna Sequences ◽  
Rna Molecules ◽  
G Quadruplex

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

scholarly journals Author Correction: De novo design of RNA-binding proteins with a prion-like domain related to ALS/FTD proteinopathies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kana Mitsuhashi ◽  
Daisuke Ito ◽  
Kyoko Mashima ◽  
Munenori Oyama ◽  
Shinichi Takahashi ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
De Novo Design

scholarly journals The design and structural characterization of a synthetic pentatricopeptide repeat protein

2015 ◽  
Vol 71 (2) ◽  
pp. 196-208 ◽  
Author(s):  
Benjamin S. Gully ◽  
Kunal R. Shah ◽  
Mihwa Lee ◽  
Kate Shearston ◽  
Nicole M. Smith ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Specific Binding ◽  
Consensus Sequence ◽  
Pentatricopeptide Repeat ◽  
Ppr Protein ◽  
Ppr Proteins

Proteins of the pentatricopeptide repeat (PPR) superfamily are characterized by tandem arrays of a degenerate 35-amino-acid α-hairpin motif. PPR proteins are typically single-stranded RNA-binding proteins with essential roles in organelle biogenesis, RNA editing and mRNA maturation. A modular, predictable code for sequence-specific binding of RNA by PPR proteins has recently been revealed, which opens the door to thede novodesign of bespoke proteins with specific RNA targets, with widespread biotechnological potential. Here, the design and production of a synthetic PPR protein based on a consensus sequence and the determination of its crystal structure to 2.2 Å resolution are described. The crystal structure displays helical disorder, resulting in electron density representing an infinite superhelical PPR protein. A structural comparison with related tetratricopeptide repeat (TPR) proteins, and with native PPR proteins, reveals key roles for conserved residues in directing the structure and function of PPR proteins. The designed proteins have high solubility and thermal stability, and can form long tracts of PPR repeats. Thus, consensus-sequence synthetic PPR proteins could provide a suitable backbone for the design of bespoke RNA-binding proteins with the potential for high specificity.

scholarly journals RNA-Binding Proteins hnRNP A2/B1 and CUGBP1 Suppress Fragile X CGG Premutation Repeat-Induced Neurodegeneration in a Drosophila Model of FXTAS

Neuron ◽  
2007 ◽  
Vol 55 (4) ◽  
pp. 565-571 ◽  
Author(s):  
Oyinkan A. Sofola ◽  
Peng Jin ◽  
Yunlong Qin ◽  
Ranhui Duan ◽  
Huijie Liu ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Drosophila Model

scholarly journals Thermodynamic modeling reveals widespread multivalent binding by RNA-binding proteins

2021 ◽  
Author(s):  
Salma Sohrabi-Jahromi ◽  
Johannes Söding
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Sequence Specificity ◽  
Rna Sequences ◽  
Link Type ◽  
Binding Domains ◽  
Regulatory Processes ◽  
Multivalent Binding

AbstractMotivationUnderstanding how proteins recognize their RNA targets is essential to elucidate regulatory processes in the cell. Many RNA-binding proteins (RBPs) form complexes or have multiple domains that allow them to bind to RNA in a multivalent, cooperative manner. They can thereby achieve higher specificity and affinity than proteins with a single RNA-binding domain. However, current approaches to de-novo discovery of RNA binding motifs do not take multivalent binding into account.ResultsWe present Bipartite Motif Finder (BMF), which is based on a thermodynamic model of RBPs with two cooperatively binding RNA-binding domains. We show that bivalent binding is a common strategy among RBPs, yielding higher affinity and sequence specificity. We furthermore illustrate that the spatial geometry between the binding sites can be learned from bound RNA sequences. These discovered bipartite motifs are consistent with previously known motifs and binding behaviors. Our results demonstrate the importance of multivalent binding for RNA-binding proteins and highlight the value of bipartite motif models in representing the multivalency of protein-RNA interactions.AvailabilityBMF source code is available at https://github.com/soedinglab/bipartite_motif_finder under a GPL license. The BMF web server is accessible at https://bmf.soedinglab.org.

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