scholarly journals Molecular basis for GIGYF-TNRC6 complex assembly in miRNA-mediated translational repression

2021 ◽  
Author(s):  
Meghna Sobti ◽  
Benjamin J. Mead ◽  
Cátia Igreja ◽  
Alastair G. Stewart ◽  
Mary Christie
Keyword(s):  
Crystal Structures ◽  
Molecular Basis ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translational Repression ◽  
Aromatic Residues ◽  
Mrna Targets ◽  
Associated Proteins ◽  
Phenylalanine Residue

AbstractThe GIGYF proteins associate with 4EHP and RNA-associated proteins to elicit transcript-specific translational repression. However, the mechanism by which the GIGYF1/2-4EHP complex is recruited to its target transcripts remain unclear. Here we report the crystal structures of the GYF domains from GIGYF1 and GIGYF2 in complex with proline-rich sequences from miRISC-binding proteins TNRC6C and TNRC6A, respectively. The TNRC6 proline-rich motifs bind to a conserved array of aromatic residues on the surface of the GIGYF1/2 GYF domain, bridging 4EHP to Argonaute-miRNA mRNA targets. Our structures also reveal a phenylalanine residue conserved from yeast to human GYF domains that contributes to GIGYF2 thermostability. The molecular details we outline here are likely to be conserved between GIGYF1/2 and other RNA-binding proteins to elicit 4EHP-mediated repression in different biological contexts.

scholarly journals CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lizhen Chen ◽  
Zhijie Liu ◽  
Bing Zhou ◽  
Chaoliang Wei ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Axon Regeneration ◽  
Rna Binding Proteins ◽  
Mrna Isoforms ◽  
C Elegans ◽  
Mrna Targets

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

scholarly journals Prediction of breast cancer proteins using molecular descriptors and artificial neural networks: a focus on cancer immunotherapy proteins, metastasis driver proteins, and RNA-binding proteins

2019 ◽  
Author(s):  
Andrés López-Cortés ◽  
Alejandro Cabrera-Andrade ◽  
José M. Vázquez-Naya ◽  
Alejandro Pazos ◽  
Humberto Gonzáles-Díaz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neural Networks ◽  
Cancer Immunotherapy ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Operating Characteristics ◽  
Associated Proteins ◽  
Artificial Neural ◽  
New Biomarkers

ABSTRACTBackgroundBreast cancer (BC) is a heterogeneous disease characterized by an intricate interplay between different biological aspects such as ethnicity, genomic alterations, gene expression deregulation, hormone disruption, signaling pathway alterations and environmental determinants. Due to the complexity of BC, the prediction of proteins involved in this disease is a trending topic in drug design.MethodsThis work is proposing accurate prediction classifier for BC proteins using six sets of protein sequence descriptors and 13 machine learning methods. After using a univariate feature selection for the mix of five descriptor families, the best classifier was obtained using multilayer perceptron method (artificial neural network) and 300 features.ResultsThe performance of the model is demonstrated by the area under the receiver operating characteristics (AUROC) of 0.980 ± 0.0037 and accuracy of 0.936 ± 0.0056 (3-fold cross-validation). Regarding the prediction of 4504 cancer-associated proteins using this model, the best ranked cancer immunotherapy proteins related to BC were RPS27, SUPT4H1, CLPSL2, POLR2K, RPL38, AKT3, CDK3, RPS20, RASL11A and UBTD1; the best ranked metastasis driver proteins related to BC were S100A9, DDA1, TXN, PRNP, RPS27, S100A14, S100A7, MAPK1, AGR3 and NDUFA13; and the best ranked RNA-binding proteins related to BC were S100A9, TXN, RPS27L, RPS27, RPS27A, RPL38, MRPL54, PPAN, RPS20 and CSRP1.ConclusionsThis powerful model predicts several BC-related proteins which should be deeply studied to find new biomarkers and better therapeutic targets. The script and the results are available as a free repository at https://github.com/muntisa/neural-networks-for-breast-cancer-proteins.

scholarly journals SPACE exploration of chromatin proteome to reveal associated RNA-binding proteins

2020 ◽  
Author(s):  
Mahmoud-Reza Rafiee ◽  
Julian A Zagalak ◽  
Giulia Tyzack ◽  
Rickie Patani ◽  
Jernej Ule ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genome Maintenance ◽  
Purification Method ◽  
Comprehensive Knowledge ◽  
Associated Proteins ◽  
Versatile Technique ◽  
Dna Binders ◽  
Lateral Sclerosis

AbstractChromatin is composed of many proteins that mediate intermolecular transactions with the genome. Comprehensive knowledge of these components and their interactions is necessary for insights into gene regulation and other activities; however, reliable identification of chromatin-associated proteins remains technically challenging. Here, we present SPACE (Silica Particle Assisted Chromatin Enrichment), a stringent and straightforward chromatin-purification method that helps identify direct DNA-binders separately from chromatin-associated proteins. We demonstrate SPACE’s unique strengths in three experimental set-ups: the sensitivity to detect novel chromatin-associated proteins, the quantitative nature to measure dynamic protein use across distinct cellular conditions, and the ability to handle 10-25 times less starting material than competing methods. In doing so, we reveal an unforeseen scale of association between over 500 nuclear RNA-binding proteins (RBPs) with chromatin and DNA, providing new insights into their roles as important regulators of genome maintenance and chromatin composition. Applied to iPSC-derived neural precursors, we discover a new role for the amyotrophic lateral sclerosis (ALS)-causing Valosin Containing Protein (VCP) in recruiting DNA-damage components to chromatin, thus paving the way for molecular mechanistic insights into the disease. SPACE is a fast and versatile technique with many applications.

scholarly journals Functional Roles of RNA-Binding Proteins in Plant Signaling

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 288
Author(s):  
Victor Muleya ◽  
Claudius Marondedze
Keyword(s):  
Stress Responses ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Structural Similarity ◽  
Plant Signaling ◽  
Affinity Capture ◽  
Functional Roles ◽  
Binding Domains ◽  
Mrna Targets

RNA-binding proteins (RBPs) are typical proteins that bind RNA through single or multiple RNA-binding domains (RBDs). These proteins have a functional role in determining the fate or function of the bound RNAs. A few hundred RBPs were known through in silico prediction based on computational assignment informed by structural similarity and the presence of classical RBDs. However, RBPs lacking such conventional RBDs were omitted. Owing to the recent mRNA interactome capture technology based on UV-crosslinking and fixing proteins to their mRNA targets followed by affinity capture purification and identification of RBPs by tandem mass spectrometry, several hundreds of RBPs have recently been discovered. These proteome-wide studies have colossally increased the number of proteins implicated in RNA binding and unearthed hundreds of novel RBPs lacking classical RBDs, such as proteins involved in intermediary metabolism. These discoveries provide wide insights into the post-transcriptional gene regulation players and their role in plant signaling, such as environmental stress conditions. In this review, novel discoveries of RBPs are explored, particularly on the evolving knowledge of their role in stress responses. The molecular functions of these RBPs, particularly focusing on those that do not have classical RBDs, are also elucidated at the systems level.

167. MUSASHI FAMILY OF RNA BINDING PROTEINS: CELL CYCLE REGULATORS IN SPERMATOGENESIS

2010 ◽  
Vol 22 (9) ◽  
pp. 85
Author(s):  
E. A. McLaughlin ◽  
B. A. Fraser ◽  
V. Pye ◽  
M. Bigland ◽  
N. A. Siddall ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Differentiation ◽  
Germ Cell ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translational Repression ◽  
Germ Cell Differentiation ◽  
Pachytene Spermatocytes

Mammalian meiosis is a tightly regulated process involving specialized cell cycle progression and morphogenetic changes. We have demonstrated that the Musashi family of RNA binding proteins is implicated in the regulation of spermatogonial stem self renewal and germ cell differentiation. Here we describe the novel mechanism by which the Musashi family proteins, Msi1 and Msi2, act to control exit from spermatogonial mitotic amplification and normal entry into meiosis. Gene and protein analysis indicated overlapping Msi1 and Msi2 profiles in enriched populations of isolated germ cells and reciprocal subcellular expression patterns in spermatogonia and pachytene spermatocytes/ round spermatids in testes sections. Recombinant Msi1 protein-RNA pulldown and microarray analysis coupled with in vitro shRNA knockdown studies in spermatogonial culture and subsequent immunoprecipitation and qPCR established that Msi1 targeted Msi2 mRNA for post transcriptional translational repression. Immunoprecipitation of Msi2 target mRNA and subsequent qPCR together with in vitro shRNA knockdown studies inround spermatidculture identified a cell cycle inhibitor protein CDKN1C (p57kip2) as the principal target of Msi2 translational inhibition. Immunolocalisation of CDKN1C protein indicated that expression of this cell cycle regulator coincided with the nuclear import of Msi1 and the appearance of cytoplasmic Msi2 expression in early pachytene spermatocytes. Using a transgenic Msi1 overexpression mouse model in conjunction with quantitative gene and protein expression, we confirmed Msi1 targeting of Msi2 and subsequent Msi2 targeting of CDKN1C for translational repression in vivo. Ectopic overexpression of Msi1 in germ cellsinduces substantial Msi2 downregulation and aberrant CDKN1C expression, resulting in abnormal spermatogenic differentiation, germ cell apoptosis/arrest and sterility. In conclusion, our results indicate a sophisticated molecular switch encompassing cell cycle protein regulation by Musashi family proteins, is required for normal exit from mitotic division, entry into meiosis and post meiotic germ cell differentiation.

scholarly journals Versatility of RNA-Binding Proteins in Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Laurence Wurth
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Tumor Development ◽  
Posttranscriptional Control ◽  
Master Regulators ◽  
Binding Domains ◽  
Mrna Targets ◽  
Posttranscriptional Gene Regulation ◽  
A Cell

Posttranscriptional gene regulation is a rapid and efficient process to adjust the proteome of a cell to a changing environment. RNA-binding proteins (RBPs) are the master regulators of mRNA processing and translation and are often aberrantly expressed in cancer. In addition to well-studied transcription factors, RBPs are emerging as fundamental players in tumor development. RBPs and their mRNA targets form a complex network that plays a crucial role in tumorigenesis. This paper describes mechanisms by which RBPs influence the expression of well-known oncogenes, focusing on precise examples that illustrate the versatility of RBPs in posttranscriptional control of cancer development. RBPs appeared very early in evolution, and new RNA-binding domains and combinations of them were generated in more complex organisms. The identification of RBPs, their mRNA targets, and their mechanism of action have provided novel potential targets for cancer therapy.

scholarly journals Evolutionary Conservation and Diversification of Puf RNA Binding Proteins and Their mRNA Targets

PLoS Biology ◽  
2015 ◽  
Vol 13 (11) ◽  
pp. e1002307 ◽  
Author(s):  
Gregory J. Hogan ◽  
Patrick O. Brown ◽  
Daniel Herschlag
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Evolutionary Conservation ◽  
Mrna Targets

scholarly journals Essential PBP1-associated proteins of Trypanosoma brucei

2020 ◽  
Author(s):  
L. Nascimento ◽  
M. Terrao ◽  
KK. Marucha ◽  
B. Liu ◽  
F. Egler ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Ribosomal Proteins ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Low Complexity ◽  
Control Of Gene Expression ◽  
C Terminus ◽  
Associated Proteins ◽  
A Minor

AbstractControl of gene expression in kinetoplastids depends heavily on RNA-binding proteins that influence mRNA decay and translation. We previously showed that MKT1 interacts with PBP1, which in turn recruits LSM12 and poly(A) binding protein. MKT1 is recruited to mRNA by sequence-specific RNA-binding proteins, resulting in stabilisation of mRNA. We here show that PBP1, LSM12 and an additional 117-residue protein, XAC1 (Tb927.7.2780), are present in complexes that contain either MKT1 or MKT1L (Tb927.10.1490). All five proteins are present predominantly in the complexes, and there was evidence for a minor subset of complexes that contained both MKT1 and MKT1L. MKT1 appeared to be associated with many mRNAs, with the exception of those encoding ribosomal proteins. XAC1-containing complexes reproducibly contained RNA-binding proteins that were previously found associated with MKT1. In addition, however, XAC1- or MKT1-containing complexes specifically recruit one of the six translation initiation complexes, EIF4E6-EIF4G5; and yeast 2-hybrid assay results indicated that MKT1 interacts with EIF4G5. The C-terminus of MKT1L resembles MKT1: it contains MKT1 domains and a PIN domain that is probably not active as an endonuclease. MKT1L, however, also has an N-terminal extension with regions of low-complexity. Although MKT1L depletion inhibited cell proliferation, we found no evidence for specific interactions with RNA-binding proteins or mRNA. Deletion of the N-terminal extension, however, enabled MKT1L to interact with EIF4E6. We speculate that MKT1L may either enhance or inhibit the functions of MKT1-containing complexes.

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