Key Points
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Novel proteome-wide approaches, in particular RNA interactome capture, have largely expanded the repertoire of known RNA-binding proteins (RBPs)
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Newly discovered RBPs generally lack canonical RNA-binding domains (RBDs) and are functionally diverse. These unconventional RBPs are conserved from yeast to humans and respond to environmental and physiological cues
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A variety of protein domains endowed with RNA-binding activity have recently been discovered, including DNA-binding domains, protein–protein interaction interfaces, enzymatic cores and intrinsically disordered regions. These domains are prone to post-translational modifications and represent disease mutation hot spots
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The identification of unconventional RBPs and their unconventional RBDs suggests the existence of previously unidentified modes of RNA binding and new biological functions for protein–RNA interactions
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RNA control of protein function may occur more commonly than previously anticipated
Abstract
RNA-binding proteins (RBPs) are typically thought of as proteins that bind RNA through one or multiple globular RNA-binding domains (RBDs) and change the fate or function of the bound RNAs. Several hundred such RBPs have been discovered and investigated over the years. Recent proteome-wide studies have more than doubled the number of proteins implicated in RNA binding and uncovered hundreds of additional RBPs lacking conventional RBDs. In this Review, we discuss these new RBPs and the emerging understanding of their unexpected modes of RNA binding, which can be mediated by intrinsically disordered regions, protein–protein interaction interfaces and enzymatic cores, among others. We also discuss the RNA targets and molecular and cellular functions of the new RBPs, as well as the possibility that some RBPs may be regulated by RNA rather than regulate RNA.
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Acknowledgements
The authors dedicate this Review to the memory of B. Fischer, who sadly passed away while this Review was in preparation. The authors are grateful to the members of their laboratories for helpful discussions throughout. The authors also acknowledge research funding from the European Research Council (ERC-2011-ADG_20110310; M.W.H.), a UK Medical Research Council Career Development Award (MR/L019434/1; A.C), the European Molecular Biology Laboratory Interdisciplinary Postdoctoral 2 Programme (EIPOD2/291772; T.S.) and the Australian National Health and Medical Research Council (APP1120483; M.W.H. and T.P.).
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Supplementary information
Supplementary information S1 (figure)
Comparison of RNA interactome capture data with in silico methods to identify RNA-binding proteins (RBPs). (PDF 200 kb)
Supplementary information S2 (table)
This table contains high-throughput detection screens for RNA-binding proteins (XLSX 603 kb)
Glossary
- RNA recognition motif
-
(RRM). An RNA-binding domain of ∼90 amino acids that folds into two α-helices packed against a four-stranded β-sheet, which interact with RNA.
- hnRNP K homology domain
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(KH). An RNA-binding domain of ∼70 amino acids that folds into three α-helices packed against a three-stranded β-sheet. RNA binds to a hydrophobic cleft formed between two core α-helices and a GXXG loop that interconnects them.
- DEAD box helicase
-
RNA helicases with two highly similar domains that resemble the bacterial recombinase A and contain the conserved sequence Asp-Glu-Ala-Asp (DEAD). RNA binds across both helicase domains.
- Epitranscriptome
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The collective, chemically diverse RNA modifications found in a transcriptome. Many of the modifications serve regulatory roles.
- Cajal bodies
-
Subnuclear membrane-less structures involved in multiple aspects of nuclear RNA metabolism.
- Paraspeckles
-
Ribonucleoprotein particles of poorly defined function in the nucleoplasm of mammalian cells.
- Processing (P−) bodies
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Microscopically visible foci in the cytoplasm of eukaryotic cells that contain mRNAs and mRNA silencing and turnover factors.
- Stress granules
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Cytoplasmic aggregates of stalled translation initiation complexes in eukaryotic cells that are induced by different forms of cellular stress.
- Liquid–liquid phase separation
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A (bio)physical process whereby membrane-less compartments are formed within cells as phase-separated, liquid-like droplets.
- Intrinsically disordered regions
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(IDRs). Areas within native proteins that lack stable secondary or tertiary structure and thus appear unfolded.
- Long non-coding RNAs
-
(lncRNAs). RNAs longer than 200 nucleotides without annotated protein-coding potential.
- Ultraviolet crosslinking
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A method that uses ultraviolet light irradiation in vitro or in living cells to covalently connect proteins and RNA that are positioned in very close proximity to each other.
- Zinc-finger domains
-
Zinc-binding protein domains that can mediate interactions with DNA, RNA or proteins, depending on their subclass.
- Intermediary metabolism
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A collective term for metabolic processes that convert nutrients into cellular components.
- InParanoid analysis
-
A method for detecting orthologues and in-paralogue gene clusters across different, often distant species.
- UpSet plot
-
A plot used to visualize the total size and overlaps of various data sets.
- BioPlex PPI data set
-
A comprehensive collection of protein–protein interaction networks generated by experimental approaches.
- Maternal-to-zygotic transition
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(MZT). The phase in embryonic development during which control by maternally derived factors ceases and the zygotic genome is activated.
- Electrophoretic mobility shift assay
-
(EMSA). A method to study protein–nucleic acid interactions in vitro by resolving a labelled nucleic acid probe and its binding proteins on the basis of the reduced mobility of the probe–protein complexes through a nondenaturing gel.
- RNPxl
-
Custom-designed software to facilitate the identification of mass spectra derived from a peptide crosslinked to a nucleotide.
- G-Quadruplexes
-
Nucleic acid structures made of two or more stacks of planar arrays of four guanine bases.
- RNA aptamers
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Relatively short and often highly folded RNA molecules, which are selected for specific, high-affinity interactions with proteins or other molecules.
- Rossmann-fold
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(R-f). A protein domain with up to seven mostly parallel β-strands combined with connecting α-helices. Typically found in proteins that bind nucleotides.
- RNase P complex
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An RNase complex that processes precursor tRNA.
- Speckles
-
Nucleoplasmic granules located at interchromatin regions that are enriched in splicing factors
- Polyuridylation
-
The addition of multiple uridines to the 3′ end of RNA molecules by uridylyltransferases as a signal for RNA degradation.
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Hentze, M., Castello, A., Schwarzl, T. et al. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol 19, 327–341 (2018). https://doi.org/10.1038/nrm.2017.130
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DOI: https://doi.org/10.1038/nrm.2017.130
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