scholarly journals Targeting RNA Binding Proteins Involved in Neurodegeneration

2013 ◽  
Vol 18 (9) ◽  
pp. 967-983 ◽  
Author(s):  
Maurizio Romano ◽  
Emanuele Buratti
Keyword(s):  
Protein Interactions ◽  
Rna Processing ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Correct Identification ◽  
Protein Protein Interactions ◽  
Aggregation Processes ◽  
Cellular Pathways ◽  
Screening Approaches

Dysfunctions at the level of RNA processing have recently been shown to play a fundamental role in the pathogenesis of many neurodegenerative diseases. Several proteins responsible for these dysfunctions (TDP-43, FUS/TLS, and hnRNP A/Bs) belong to the nuclear class of heterogeneous ribonucleoproteins (hnRNPs) that predominantly function as general regulators of both coding and noncoding RNA metabolism. The discovery of the importance of these factors in mediating neuronal death has represented a major paradigmatic shift in our understanding of neurodegenerative processes. As a result, these discoveries have also opened the way toward novel biomolecular screening approaches in our search for therapeutic options. One of the major hurdles in this search is represented by the correct identification of the most promising targets to be prioritized. These may include aberrant aggregation processes, protein-protein interactions, RNA-protein interactions, or specific cellular pathways altered by disease. In this review, we discuss these four major options together with their various advantages and drawbacks.

scholarly journals iSUMO - integrative prediction of functionally relevant SUMOylation events

2016 ◽  
Author(s):  
Xiaotong Yao ◽  
Shuvadeep Maity ◽  
Shashank Gandhi ◽  
Marcin Imielenski ◽  
Christine Vogel
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
False Positive Rate ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Positive Rate ◽  
Protein Nucleic Acid ◽  
Scale Experiment

AbstractPost-translational modifications by the Small Ubiquitin-like Modifier (SUMO) are essential for diverse cellular functions. Large-scale experiment and sequence-based predictions have identified thousands of SUMOylated proteins. However, the overlap between the datasets is small, suggesting many false positives with low functional relevance. Therefore, we integrated ~800 sequence features and protein characteristics such as cellular function and protein-protein interactions in a machine learning approach to score likely functional SUMOylation events (iSUMO). iSUMO is trained on a total of 24 large-scale datasets, and it predicts 2,291 and 706 SUMO targets in human and yeast, respectively. These estimates are five times higher than what existing sequence-based tools predict at the same 5% false positive rate. Protein-protein and protein-nucleic acid interactions are highly predictive of protein SUMOylation, supporting a role of the modification in protein complex formation. We note the marked prevalence of SUMOylation amongst RNA-binding proteins. We validate iSUMO predictions by experimental or other evidence. iSUMO therefore represents a comprehensive tool to identify high-confidence, functional SUMOylation events for human and yeast.

scholarly journals Capturing RNA–protein interaction via CRUIS

2020 ◽  
Vol 48 (9) ◽  
pp. e52-e52 ◽  
Author(s):  
Ziheng Zhang ◽  
Weiping Sun ◽  
Tiezhu Shi ◽  
Pengfei Lu ◽  
Min Zhuang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Dna Damage ◽  
Protein Interactions ◽  
Noncoding Rna ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Living Cells ◽  
Innovative Methods ◽  
Rna Biology

Abstract No RNA is completely naked from birth to death. RNAs function with and are regulated by a range of proteins that bind to them. Therefore, the development of innovative methods for studying RNA–protein interactions is very important. Here, we developed a new tool, the CRISPR-based RNA-United Interacting System (CRUIS), which captures RNA–protein interactions in living cells by combining the power of CRISPR and PUP-IT, a novel proximity targeting system. In CRUIS, dCas13a is used as a tracker to target specific RNAs, while proximity enzyme PafA is fused to dCas13a to label the surrounding RNA-binding proteins, which are then identified by mass spectrometry. To identify the efficiency of CRUIS, we employed NORAD (Noncoding RNA activated by DNA damage) as a target, and the results show that a similar interactome profile of NORAD can be obtained as by using CLIP (crosslinking and immunoprecipitation)-based methods. Importantly, several novel NORAD RNA-binding proteins were also identified by CRUIS. The use of CRUIS facilitates the study of RNA–protein interactions in their natural environment, and provides new insights into RNA biology.

scholarly journals rec-Y2H matrix screening reveals a vast potential for direct protein-protein interactions among RNA binding proteins

2020 ◽  
Author(s):  
Benjamin Lang ◽  
Jae-Seong Yang ◽  
Mireia Garriga-Canut ◽  
Silvia Speroni ◽  
Maria Gili ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Interaction Networks ◽  
Sequence Motifs ◽  
Protein Protein Interactions ◽  
Binding Interaction ◽  
Transcriptional Gene Regulation

AbstractRNA-binding proteins (RBPs) are crucial factors of post-transcriptional gene regulation and their modes of action are intensely investigated. At the center of attention are RNA motifs that guide where RBPs bind. However, sequence motifs are often poor predictors of RBP-RNA interactions in vivo. It is hence believed that many RBPs recognize RNAs as complexes, to increase specificity and regulatory possibilities. To probe the potential for complex formation among RBPs, we assembled a library of 978 mammalian RBPs and used rec-Y2H screening to detect direct interactions between RBPs, sampling > 600 K interactions. We discovered 1994 new interactions and demonstrate that interacting RBPs bind RNAs adjacently in vivo. We further find that the mRNA binding region and motif preferences of RBPs can deviate, depending on their adjacently binding interaction partners. Finally, we reveal novel RBP interaction networks among major RNA processing steps and show that splicing impairing RBP mutations observed in cancer rewire spliceosomal interaction networks.Graphical abstract

scholarly journals Interactions between the double-stranded RNA-binding proteins TRBP and PACT define the Medipal domain that mediates protein-protein interactions

RNA Biology ◽  
2008 ◽  
Vol 5 (2) ◽  
pp. 92-103 ◽  
Author(s):  
Ghislaine Laraki ◽  
Guerline Clerzius ◽  
Aïcha Daher ◽  
Carlos Melendez-Peña ◽  
Sylvanne Daniels ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Protein Interactions ◽  
Double Stranded Rna

scholarly journals CircRNA—Protein Interactions in Muscle Development and Diseases

2021 ◽  
Vol 22 (6) ◽  
pp. 3262
Author(s):  
Shuailong Zheng ◽  
Xujia Zhang ◽  
Emmanuel Odame ◽  
Xiaoli Xu ◽  
Yuan Chen ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Noncoding Rna ◽  
Muscle Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Normal Animal ◽  
Circular Rna ◽  
Future Application ◽  
Animal Development ◽  
Mrna Precursor

Circular RNA (circRNA) is a kind of novel endogenous noncoding RNA formed through back-splicing of mRNA precursor. The biogenesis, degradation, nucleus–cytoplasm transport, location, and even translation of circRNA are controlled by RNA-binding proteins (RBPs). Therefore, circRNAs and the chaperoned RBPs play critical roles in biological functions that significantly contribute to normal animal development and disease. In this review, we systematically characterize the possible molecular mechanism of circRNA–protein interactions, summarize the latest research on circRNA–protein interactions in muscle development and myocardial disease, and discuss the future application of circRNA in treating muscle diseases. Finally, we provide several valid prediction methods and experimental verification approaches. Our review reveals the significance of circRNAs and their protein chaperones and provides a reference for further study in this field.

scholarly journals Plant Ribonuclease J: An Essential Player in Maintaining Chloroplast RNA Quality Control for Gene Expression

Plants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 334
Author(s):  
Amber M. Hotto ◽  
David B. Stern ◽  
Gadi Schuster
Keyword(s):  
Gene Expression ◽  
Quality Control ◽  
Protein Interactions ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Land Plant ◽  
Protein Protein Interactions ◽  
Rna Quality ◽  
Rna Quality Control ◽  
Chloroplast Rna

RNA quality control is an indispensable but poorly understood process that enables organisms to distinguish functional RNAs from nonfunctional or inhibitory ones. In chloroplasts, whose gene expression activities are required for photosynthesis, retrograde signaling, and plant development, RNA quality control is of paramount importance, as transcription is relatively unregulated. The functional RNA population is distilled from this initial transcriptome by a combination of RNA-binding proteins and ribonucleases. One of the key enzymes is RNase J, a 5′→3′ exoribonuclease and an endoribonuclease that has been shown to trim 5′ RNA termini and eliminate deleterious antisense RNA. In the absence of RNase J, embryo development cannot be completed. Land plant RNase J contains a highly conserved C-terminal domain that is found in GT-1 DNA-binding transcription factors and is not present in its bacterial, archaeal, and algal counterparts. The GT-1 domain may confer specificity through DNA and/or RNA binding and/or protein–protein interactions and thus be an element in the mechanisms that identify target transcripts among diverse RNA populations. Further understanding of chloroplast RNA quality control relies on discovering how RNase J is regulated and how its specificity is imparted.

scholarly journals Screening Approaches for Targeting Ribonucleoprotein Complexes: A New Dimension for Drug Discovery

2019 ◽  
Vol 24 (3) ◽  
pp. 314-331 ◽  
Author(s):  
Vito Giuseppe D’Agostino ◽  
Denise Sighel ◽  
Chiara Zucal ◽  
Isabelle Bonomo ◽  
Mariachiara Micaelli ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Posttranscriptional Control ◽  
Control Of Gene Expression ◽  
Ribonucleoprotein Complexes ◽  
Screening Approaches

RNA-binding proteins (RBPs) are pleiotropic factors that control the processing and functional compartmentalization of transcripts by binding primarily to mRNA untranslated regions (UTRs). The competitive and/or cooperative interplay between RBPs and an array of coding and noncoding RNAs (ncRNAs) determines the posttranscriptional control of gene expression, influencing protein production. Recently, a variety of well-recognized and noncanonical RBP domains have been revealed by modern system-wide analyses, underlying an evolving classification of ribonucleoproteins (RNPs) and their importance in governing physiological RNA metabolism. The possibility of targeting selected RNA–protein interactions with small molecules is now expanding the concept of protein “druggability,” with new implications for medicinal chemistry and for a deeper characterization of the mechanism of action of bioactive compounds. Here, taking SF3B1, HuR, LIN28, and Musashi proteins as paradigmatic case studies, we review the strategies applied for targeting RBPs, with emphasis on the technological advancements to study protein–RNA interactions and on the requirements of appropriate validation strategies to parallel high-throughput screening (HTS) efforts.

scholarly journals The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

2016 ◽  
Vol 473 (23) ◽  
pp. 4271-4288 ◽  
Author(s):  
Michael Norman ◽  
Caroline Rivers ◽  
Youn-Bok Lee ◽  
Jalilah Idris ◽  
James Uney
Keyword(s):  
Protein Interactions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cellular Stress Response ◽  
Regulatory Rna ◽  
Protein Protein Interactions ◽  
Attachment Region ◽  
Dna Elements ◽  
Scaffold Attachment Region

RNA-binding proteins play a central role in cellular metabolism by orchestrating the complex interactions of coding, structural and regulatory RNA species. The SAFB (scaffold attachment factor B) proteins (SAFB1, SAFB2 and SAFB-like transcriptional modulator, SLTM), which are highly conserved evolutionarily, were first identified on the basis of their ability to bind scaffold attachment region DNA elements, but attention has subsequently shifted to their RNA-binding and protein–protein interactions. Initial studies identified the involvement of these proteins in the cellular stress response and other aspects of gene regulation. More recently, the multifunctional capabilities of SAFB proteins have shown that they play crucial roles in DNA repair, processing of mRNA and regulatory RNA, as well as in interaction with chromatin-modifying complexes. With the advent of new techniques for identifying RNA-binding sites, enumeration of individual RNA targets has now begun. This review aims to summarise what is currently known about the functions of SAFB proteins.

scholarly journals CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

2021 ◽  
Vol 22 (20) ◽  
pp. 11056
Author(s):  
Maryam Nasiri-Aghdam ◽  
Texali C. Garcia-Garduño ◽  
Luis Felipe Jave-Suárez
Keyword(s):  
Alternative Splicing ◽  
Rna Processing ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cancer Proliferation ◽  
Functional Consequences ◽  
Rna Biogenesis ◽  
Non Coding Rnas ◽  
Proliferation And Invasion

Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

scholarly journals Transcriptome-wide identification of coding and noncoding RNA-binding proteins defines the comprehensive RNA interactome of Leishmania mexicana

2021 ◽  
Author(s):  
Karunakaran Kalesh ◽  
Wenbin Wei ◽  
Brian S. Mantilla ◽  
Theodoros I. Roumeliotis ◽  
Jyoti Choudhary ◽  
...  
Keyword(s):  
Life Cycle ◽  
Protein Interactions ◽  
Ribosomal Proteins ◽  
Noncoding Rna ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Domain ◽  
Hsp90 Inhibition ◽  
Life Cycle Stages

Proteomic profiling of RNA-binding proteins in Leishmania is currently limited to polyadenylated mRNA-binding proteins, leaving proteins that interact with nonadenylated RNAs, including noncoding RNAs and pre-mRNAs, unidentified. Using a combination of unbiased orthogonal organic phase separation methodology and tandem mass tag-labelling-based high resolution quantitative proteomic mass spectrometry, we robustly identified 2,417 RNA-binding proteins, including 1289 putative novel non-poly(A)-RNA-binding proteins across the two main Leishmania life cycle stages. Eight out of twenty Leishmania deubiquitinases including the recently characterised L. mexicana DUB2 with an elaborate RNA-binding protein interactome were exclusively identified in the non-poly(A)-RNA-interactome. Additionally, an increased representation of WD40 repeat domains were observed in the Leishmania non-poly(A)-RNA-interactome, thus uncovering potential involvement of this protein domain in RNA-protein interactions in Leishmania. We also characterise the protein-bound RNAs using RNA-sequencing and show that in addition to protein coding transcripts ncRNAs are also enriched in the protein-RNA interactome. Differential gene expression analysis revealed enrichment of 145 out of 195 total L. mexicana protein kinase genes in the protein-RNA-interactome, suggesting important role of protein-RNA interactions in the regulation of the Leishmania protein kinome. Additionally, we characterise the quantitative changes in RNA-protein interactions in hundreds of Leishmania proteins following inhibition of heat shock protein 90 (Hsp90). Our results show that the Hsp90 inhibition in Leishmania causes widespread disruption of RNA-protein interactions in ribosomal proteins, proteasomal proteins and translation factors in both life cycle stages, suggesting downstream effect of the inhibition on protein synthesis and degradation pathways in Leishmania. This study defines the comprehensive RNA interactome of Leishmania and provides in-depth insight into the widespread involvement of RNA-protein interactions in Leishmania biology.

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