FMRP and MicroRNAs in Neuronal Protein Synthesis

2018 ◽  
Author(s):  
Monica C. Lannom ◽  
Stephanie Ceman
Keyword(s):  
Protein Synthesis ◽  
Binding Proteins ◽  
Neuronal Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Post Translational Modifications ◽  
Local Protein Synthesis ◽  
Recognition Element ◽  
Neuronal Protein ◽  
And Function

New protein synthesis is critical for learning and memory. The discovery of ribosomes at synapses indicated the potential for local protein synthesis in response to stimulation. miRNAs play a key role in this process as evidenced by their role in normal neuronal development and function and in neurological disease. miRNA production is regulated and once bound by AGO2, the ensuing RISC complex is able to bind mRNAs and direct their translation suppression and degradation. However, other RNA binding proteins, including FMRP and MOV10, regulate AGO2 association with the miRNA recognition element (MRE) in target mRNAs. AGO2 itself is regulated by post-translational modifications, and neuronal activity controls post-translational modifications of FMRP and MOV10 that lead to their regulation and degradation. In addition, RNA localization at the synapse is a critical regulated event that depends on both cis sequences in the mRNA and the identity of the bound RNA binding proteins.

The expanding world of metabolic enzymes moonlighting as RNA binding proteins

2021 ◽  
Author(s):  
Nicole J. Curtis ◽  
Constance J. Jeffery
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Molecular Structures ◽  
Intermediary Metabolism ◽  
The Many ◽  
And Function

RNA binding proteins play key roles in many aspects of RNA metabolism and function, including splicing, transport, translation, localization, stability and degradation. Within the past few years, proteomics studies have identified dozens of enzymes in intermediary metabolism that bind to RNA. The wide occurrence and conservation of RNA binding ability across distant branches of the evolutionary tree suggest that these moonlighting enzymes are involved in connections between intermediary metabolism and gene expression that comprise far more extensive regulatory networks than previously thought. There are many outstanding questions about the molecular structures and mechanisms involved, the effects of these interactions on enzyme and RNA functions, and the factors that regulate the interactions. The effects on RNA function are likely to be wider than regulation of translation, and some enzyme–RNA interactions have been found to regulate the enzyme's catalytic activity. Several enzyme–RNA interactions have been shown to be affected by cellular factors that change under different intracellular and environmental conditions, including concentrations of substrates and cofactors. Understanding the molecular mechanisms involved in the interactions between the enzymes and RNA, the factors involved in regulation, and the effects of the enzyme–RNA interactions on both the enzyme and RNA functions will lead to a better understanding of the role of the many newly identified enzyme–RNA interactions in connecting intermediary metabolism and gene expression.

scholarly journals Middle-down proteomics reveals dense sites of methylation and phosphorylation in arginine-rich RNA-binding proteins

2019 ◽  
Author(s):  
Sean R. Kundinger ◽  
Isaac Bishof ◽  
Eric B. Dammer ◽  
Duc M. Duong ◽  
Nicholas T. Seyfried
Keyword(s):  
Binding Proteins ◽  
Electron Transfer Dissociation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Metabolism ◽  
Hek293 Cells ◽  
Motif Analysis ◽  
Proteomic Approach ◽  
Nuclear Extracts ◽  
And Function

AbstractArginine (Arg)-rich RNA-binding proteins play an integral role in RNA metabolism. Post-translational modifications (PTMs) within Arg-rich domains, such as phosphorylation and methylation, regulate multiple steps in RNA metabolism. However, the identification of PTMs within Arg-rich domains with complete trypsin digestion is extremely challenging due to the high density of Arg residues within these proteins. Here, we report a middle-down proteomic approach coupled with electron transfer dissociation (ETD) mass spectrometry to map previously unknown sites of phosphorylation and methylation within the Arg-rich domains of U1-70K and structurally similar RNA-binding proteins from nuclear extracts of HEK293 cells. Remarkably, the Arg-rich domains in RNA-binding proteins are densely modified by methylation and phosphorylation compared with the remainder of the proteome, with di-methylation and phosphorylation favoring RSRS motifs. Although they favor a common motif, analysis of combinatorial PTMs within RSRS motifs indicate that phosphorylation and methylation do not often co-occur, suggesting they may functionally oppose one another. Collectively, these findings suggest that the level of PTMs within Arg-rich domains may be among the highest in the proteome, and a possible unexplored regulator of RNA metabolism. These data also serve as a resource to facilitate future mechanistic studies of the role of PTMs in RNA-binding protein structure and function.BriefsMiddle-down proteomics reveals arginine-rich RNA-binding proteins contain many sites of methylation and phosphorylation.

scholarly journals The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

2021 ◽  
Vol 14 ◽  
Author(s):  
María Landínez-Macías ◽  
Olivier Urwyler
Keyword(s):  
Nervous System ◽  
Binding Proteins ◽  
Neuronal Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Axon Growth ◽  
Rna Metabolism ◽  
Nervous System Development ◽  
Protein Isoforms ◽  
Growth Guidance

Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

scholarly journals Circular RNAs: Biogenesis, Mechanism, and Function in Human Cancers

2019 ◽  
Vol 20 (16) ◽  
pp. 3926 ◽  
Author(s):  
Xing Zhao ◽  
Yujie Cai ◽  
Jianzhen Xu
Keyword(s):  
Noncoding Rna ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cancer Development ◽  
Circular Rnas ◽  
Open Questions ◽  
Circular Configuration ◽  
And Function

CircRNAs are a class of noncoding RNA species with a circular configuration that is formed by either typical spliceosome-mediated or lariat-type splicing. The expression of circRNAs is usually abnormal in many cancers. Several circRNAs have been demonstrated to play important roles in carcinogenesis. In this review, we will first provide an introduction of circRNAs biogenesis, especially the regulation of circRNA by RNA-binding proteins, then we will focus on the recent findings of circRNA molecular mechanisms and functions in cancer development. Finally, some open questions are also discussed.

scholarly journals Plasticity of nuclear and cytoplasmic stress responses of RNA-binding proteins

2020 ◽  
Vol 48 (9) ◽  
pp. 4725-4740 ◽  
Author(s):  
Michael Backlund ◽  
Frank Stein ◽  
Mandy Rettel ◽  
Thomas Schwarzl ◽  
Joel I Perez-Perri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Responses ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Environmental Cues ◽  
Adaptive Responses ◽  
Stressed Cells ◽  
And Function

Abstract Cellular stress causes multifaceted reactions to trigger adaptive responses to environmental cues at all levels of the gene expression pathway. RNA-binding proteins (RBP) are key contributors to stress-induced regulation of RNA fate and function. Here, we uncover the plasticity of the RNA interactome in stressed cells, differentiating between responses in the nucleus and in the cytoplasm. We applied enhanced RNA interactome capture (eRIC) analysis preceded by nucleo-cytoplasmic fractionation following arsenite-induced oxidative stress. The data reveal unexpectedly compartmentalized RNA interactomes and their responses to stress, including differential responses of RBPs in the nucleus versus the cytoplasm, which would have been missed by whole cell analyses.

Double-stranded RNA-binding Proteins and the Control of Protein Synthesis and Cell Growth

2001 ◽  
Vol 66 (0) ◽  
pp. 485-498 ◽  
Author(s):  
L.M. PARKER ◽  
I. FIERRO-MONTI ◽  
T.W. REICHMAN ◽  
S. GUNNERY ◽  
M.B. MATHEWS
Keyword(s):  
Protein Synthesis ◽  
Cell Growth ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Double Stranded Rna
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