The role of disorder in RNA binding affinity and specificity

Most RNA-binding modules are small and bind few nucleotides. RNA-binding proteins typically attain the physiological specificity and affinity for their RNA targets by combining several RNA-binding modules. Here, we review how disordered linkers connecting RNA-binding modules govern the specificity and affinity of RNA–protein interactions by regulating the effective concentration of these modules and their relative orientation. RNA-binding proteins also often contain extended intrinsically disordered regions that mediate protein–protein and RNA–protein interactions with multiple partners. We discuss how these regions can connect proteins and RNA resulting in heterogeneous higher-order assemblies such as membrane-less compartments and amyloid-like structures that have the characteristics of multi-modular entities. The assembled state generates additional RNA-binding specificity and affinity properties that contribute to further the function of RNA-binding proteins within the cellular environment.

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Matrin3: Disorder and ALS Pathogenesis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.794646 ◽

2022 ◽

Vol 8 ◽

Author(s):

Ahmed Salem ◽

Carter J. Wilson ◽

Benjamin S. Rutledge ◽

Allison Dilliott ◽

Sali Farhan ◽

...

Keyword(s):

Nuclear Export ◽

Binding Proteins ◽

Rna Binding ◽

Nuclear Dna ◽

Neurodegenerative Disorder ◽

Rna Binding Proteins ◽

Binding Protein ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Disordered Regions

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons in the brain and spinal cord. ALS is associated with protein misfolding and inclusion formation involving RNA-binding proteins, including TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS). The 125-kDa Matrin3 is a highly conserved nuclear DNA/RNA-binding protein that is implicated in many cellular processes, including binding and stabilizing mRNA, regulating mRNA nuclear export, modulating alternative splicing, and managing chromosomal distribution. Mutations in MATR3, the gene encoding Matrin3, have been identified as causal in familial ALS (fALS). Matrin3 lacks a prion-like domain that characterizes many other ALS-associated RNA-binding proteins, including TDP-43 and FUS, however, our bioinformatics analyses and preliminary studies document that Matrin3 contains long intrinsically disordered regions that may facilitate promiscuous interactions with many proteins and may contribute to its misfolding. In addition, these disordered regions in Matrin3 undergo numerous post-translational modifications, including phosphorylation, ubiquitination and acetylation that modulate the function and misfolding of the protein. Here we discuss the disordered nature of Matrin3 and review the factors that may promote its misfolding and aggregation, two elements that might explain its role in ALS pathogenesis.

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Musashi-1: An Example of How Polyalanine Tracts Contribute to Self-Association in the Intrinsically Disordered Regions of RNA-Binding Proteins

International Journal of Molecular Sciences ◽

10.3390/ijms21072289 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2289 ◽

Cited By ~ 2

Author(s):

Tsai-Chen Chen ◽

Jie-rong Huang

Keyword(s):

Nmr Spectroscopy ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Structural Heterogeneity ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Self Association ◽

As Stress ◽

Disordered Regions

RNA-binding proteins (RBPs) have intrinsically disordered regions (IDRs) whose biophysical properties have yet to be explored to the same extent as those of the folded RNA interacting domains. These IDRs are essential to the formation of biomolecular condensates, such as stress and RNA granules, but dysregulated assembly can be pathological. Because of their structural heterogeneity, IDRs are best studied by NMR spectroscopy. In this study, we used NMR spectroscopy to investigate the structural propensity and self-association of the IDR of the RBP Musashi-1. We identified two transient α-helical regions (residues ~208–218 and ~270–284 in the IDR, the latter with a polyalanine tract). Strong NMR line broadening in these regions and circular dichroism and micrography data suggest that the two α-helical elements and the hydrophobic residues in between may contribute to the formation of oligomers found in stress granules and implicated in Alzheimer’s disease. Bioinformatics analysis suggests that polyalanine stretches in the IDRs of RBPs may have evolved to promote RBP assembly.

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Robust single-cell discovery of RNA targets of RNA binding proteins and ribosomes

10.21203/rs.3.rs-87224/v1 ◽

2020 ◽

Author(s):

Kristopher Brannan ◽

Isaac Chaim ◽

Brian Yee ◽

Ryan Marina ◽

Daniel Lorenz ◽

...

Keyword(s):

Single Cell ◽

Protein Interactions ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Single Cells ◽

Cell Types ◽

Cell Capture ◽

Rna Targets ◽

Long Read

Abstract RNA binding proteins (RBPs) are critical regulators of gene expression and RNA processing that are required for gene function. Yet, the dynamics of RBP regulation in single cells is unknown. To address this gap in understanding, we developed STAMP (Surveying Targets by APOBEC Mediated Profiling), which efficiently detects RBP-RNA interactions. STAMP does not rely on UV-crosslinking or immunoprecipitation and, when coupled with single-cell capture, can identify RBP- and cell type-specific RNA-protein interactions for multiple RBPs and cell types in single-pooled experiments. Pairing STAMP with long-read sequencing also yields RBP target sites for full-length isoforms. Finally, conducting STAMP using small ribosomal subunits (Ribo-STAMP) allows analysis of transcriptome-wide ribosome association in single cells. STAMP enables the study of RBP-RNA interactomes and translational landscapes with unprecedented cellular resolution.

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PlncRNADB: A Repository of Plant lncRNAs and lncRNA-RBP Protein Interactions

Current Bioinformatics ◽

10.2174/1574893614666190131161002 ◽

2019 ◽

Vol 14 (7) ◽

pp. 621-627 ◽

Cited By ~ 3

Author(s):

Youhuang Bai ◽

Xiaozhuan Dai ◽

Tiantian Ye ◽

Peijing Zhang ◽

Xu Yan ◽

...

Keyword(s):

Protein Interactions ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Populus Trichocarpa ◽

Noncoding Rnas ◽

Reference Database ◽

Protein Coding ◽

Arabidopsis Lyrata ◽

User Friendly

Background: Long noncoding RNAs (lncRNAs) are endogenous noncoding RNAs, arbitrarily longer than 200 nucleotides, that play critical roles in diverse biological processes. LncRNAs exist in different genomes ranging from animals to plants. Objective: PlncRNADB is a searchable database of lncRNA sequences and annotation in plants. Methods: We built a pipeline for lncRNA prediction in plants, providing a convenient utility for users to quickly distinguish potential noncoding RNAs from protein-coding transcripts. Results: More than five thousand lncRNAs are collected from four plant species (Arabidopsis thaliana, Arabidopsis lyrata, Populus trichocarpa and Zea mays) in PlncRNADB. Moreover, our database provides the relationship between lncRNAs and various RNA-binding proteins (RBPs), which can be displayed through a user-friendly web interface. Conclusion: PlncRNADB can serve as a reference database to investigate the lncRNAs and their interaction with RNA-binding proteins in plants. The PlncRNADB is freely available at http://bis.zju.edu.cn/PlncRNADB/.

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Intrinsically disordered electronegative clusters improve stability and binding specificity of RNA-binding proteins

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100945 ◽

2021 ◽

pp. 100945

Author(s):

Steve Zaharias ◽

Zihan Zhang ◽

Kenneth Davis ◽

Talia Fargason ◽

Derek Cashman ◽

...

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Specificity ◽

Intrinsically Disordered ◽

Improve Stability

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DT-03-02: Viewing neurodegeneration beyond the tangle: The role of RNA binding proteins in Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.08.014 ◽

2013 ◽

Vol 9 ◽

pp. P847-P847

Author(s):

Benjamin Wolozin ◽

Tara Vanderweyde ◽

Liqun Liu-Yesucevitz ◽

Alpaslan Dedeoglu ◽

Leonard Petrucelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins

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SSMART: Sequence-structure motif identification for RNA-binding proteins

10.1101/287953 ◽

2018 ◽

Cited By ~ 2

Author(s):

Alina Munteanu ◽

Neelanjan Mukherjee ◽

Uwe Ohler

Keyword(s):

Binding Sites ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Sequence Motif ◽

Primary Sequence ◽

Sequence Structure ◽

Rna Targets

AbstractMotivationRNA-binding proteins (RBPs) regulate every aspect of RNA metabolism and function. There are hundreds of RBPs encoded in the eukaryotic genomes, and each recognize its RNA targets through a specific mixture of RNA sequence and structure properties. For most RBPs, however, only a primary sequence motif has been determined, while the structure of the binding sites is uncharacterized.ResultsWe developed SSMART, an RNA motif finder that simultaneously models the primary sequence and the structural properties of the RNA targets sites. The sequence-structure motifs are represented as consensus strings over a degenerate alphabet, extending the IUPAC codes for nucleotides to account for secondary structure preferences. Evaluation on synthetic data showed that SSMART is able to recover both sequence and structure motifs implanted into 3‘UTR-like sequences, for various degrees of structured/unstructured binding sites. In addition, we successfully used SSMART on high-throughput in vivo and in vitro data, showing that we not only recover the known sequence motif, but also gain insight into the structural preferences of the RBP.AvailabilitySSMART is freely available at https://ohlerlab.mdc-berlin.de/software/SSMART_137/[email protected]

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RNA Is a Double-Edged Sword in ALS Pathogenesis

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.708181 ◽

2021 ◽

Vol 15 ◽

Author(s):

Benjamin L. Zaepfel ◽

Jeffrey D. Rothstein

Keyword(s):

Motor Neurons ◽

Cortical Neurons ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Metabolism ◽

Small Subset ◽

Toxic Rna ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

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