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RNA-Binding Proteins — Structure, Function, Networks and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 17189

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Special Issue Editor

Prof. Dr. Ji-Long Liu

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Guest Editor

1. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
Interests: metabolic cell biology; cytoophidium
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

RNA is important. Considered as the earliest macromolecule, the ‘RNA world’ theory has been circulated. RNA is too versatile to work alone—it needs to partner with its close friends ‘RNA-binding proteins’.

RNA-binding proteins represent a large class of very important proteins, which play vital roles in the function of RNA from birth to death. However, some of their binding is also transient or compartmentalized, so many unknowns remain regarding the important properties of RNA-binding proteins, such as structure, function and spatiotemporal regulation.

The main purpose of this Special Issue is to update current knowledge on RNA-binding proteins—a very important topic—in combination with new technologies. There are three main aims. First, we should reflect the continuous efforts made to decipher the structure and function of RNA-binding proteins. Second, new frontiers and cutting-edge technologies should be considered. Third, we need to emphasize RNA-binding protein networks and disease implications.

We plan to collect 10–15 articles (including research articles, reviews and mini-reviews). Please feel free to submit directly to this Special Issue. We look forward to your contributions.

Prof. Dr. Ji-Long Liu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

RNA-binding protein
structure and function
RBP disease
RBP network
RNA–protein interaction

Published Papers (7 papers)

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Research

Jump to: Review

16 pages, 6999 KiB

Open AccessArticle

In Vitro Cross-Linking MS Reveals SMG1–UPF2–SMG7 Assembly as Molecular Partners within the NMD Surveillance

by Monikaben Padariya, Borivoj Vojtesek, Ted Hupp and Umesh Kalathiya

Int. J. Mol. Sci. 2024, 25(6), 3182; https://doi.org/10.3390/ijms25063182 - 10 Mar 2024

Viewed by 910

Abstract

mRNAs containing premature stop codons are responsible for various genetic diseases as well as cancers. The truncated proteins synthesized from these aberrant mRNAs are seldom detected due to the nonsense-mediated mRNA decay (NMD) pathway. Such a surveillance mechanism detects most of these aberrant mRNAs and rapidly destroys them from the pool of mRNAs. Here, we implemented chemical cross-linking mass spectrometry (CLMS) techniques to trace novel biology consisting of protein–protein interactions (PPIs) within the NMD machinery. A set of novel complex networks between UPF2 (Regulator of nonsense transcripts 2), SMG1 (Serine/threonine-protein kinase SMG1), and SMG7 from the NMD pathway were identified, among which UPF2 was found as a connection bridge between SMG1 and SMG7. The UPF2 N-terminal formed most interactions with SMG7, and a set of residues emerged from the MIF4G-I, II, and III domains docked with SMG1 or SMG7. SMG1 mediated interactions with initial residues of UPF2, whereas SMG7 formed very few interactions in this region. Modelled structures highlighted that PPIs for UPF2 and SMG1 emerged from the well-defined secondary structures, whereas SMG7 appeared from the connecting loops. Comparing the influence of cancer-derived mutations over different CLMS sites revealed that variants in the PPIs for UPF2 or SMG1 have significant structural stability effects. Our data highlights the protein–protein interface of the SMG1, UPF2, and SMG7 genes that can be used for potential therapeutic approaches. Blocking the NMD pathway could enhance the production of neoantigens or internal cancer vaccines, which could provide a platform to design potential peptide-based vaccines. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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17 pages, 3492 KiB

Open AccessArticle

Neural Isoforms of Agrin Are Generated by Reduced PTBP1−RNA Interaction Network Spanning the Neuron−Specific Splicing Regions in AGRN

by Samira Bushra, Ying-Ni Lin, Atefeh Joudaki, Mikako Ito, Bisei Ohkawara, Kinji Ohno and Akio Masuda

Int. J. Mol. Sci. 2023, 24(8), 7420; https://doi.org/10.3390/ijms24087420 - 18 Apr 2023

Viewed by 1714

Abstract

Agrin is a heparan sulfate proteoglycan essential for the clustering of acetylcholine receptors at the neuromuscular junction. Neuron−specific isoforms of agrin are generated by alternative inclusion of three exons, called Y, Z8, and Z11 exons, although their processing mechanisms remain elusive. We found, by inspection of splicing cis−elements into the human AGRN gene, that binding sites for polypyrimidine tract binding protein 1 (PTBP1) were extensively enriched around Y and Z exons. PTBP1−silencing enhanced the coordinated inclusion of Y and Z exons in human SH−SY5Y neuronal cells, even though three constitutive exons are flanked by these alternative exons. Deletion analysis using minigenes identified five PTBP1−binding sites with remarkable splicing repression activities around Y and Z exons. Furthermore, artificial tethering experiments indicated that binding of a single PTBP1 molecule to any of these sites represses nearby Y or Z exons as well as the other distal exons. The RRM4 domain of PTBP1, which is required for looping out a target RNA segment, was likely to play a crucial role in the repression. Neuronal differentiation downregulates PTBP1 expression and promotes the coordinated inclusion of Y and Z exons. We propose that the reduction in the PTPB1−RNA network spanning these alternative exons is essential for the generation of the neuron−specific agrin isoforms. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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22 pages, 3038 KiB

Open AccessArticle

Insight into the Structural Basis for Dual Nucleic Acid—Recognition by the Scaffold Attachment Factor B2 Protein

by Sophie M. Korn, Julian Von Ehr, Karthikeyan Dhamotharan, Jan-Niklas Tants, Rupert Abele and Andreas Schlundt

Int. J. Mol. Sci. 2023, 24(4), 3286; https://doi.org/10.3390/ijms24043286 - 7 Feb 2023

Viewed by 1692

Abstract

The family of scaffold attachment factor B (SAFB) proteins comprises three members and was first identified as binders of the nuclear matrix/scaffold. Over the past two decades, SAFBs were shown to act in DNA repair, mRNA/(l)ncRNA processing and as part of protein complexes with chromatin-modifying enzymes. SAFB proteins are approximately 100 kDa-sized dual nucleic acid-binding proteins with dedicated domains in an otherwise largely unstructured context, but whether and how they discriminate DNA and RNA binding has remained enigmatic. We here provide the SAFB2 DNA- and RNA-binding SAP and RRM domains in their functional boundaries and use solution NMR spectroscopy to ascribe DNA- and RNA-binding functions. We give insight into their target nucleic acid preferences and map the interfaces with respective nucleic acids on sparse data-derived SAP and RRM domain structures. Further, we provide evidence that the SAP domain exhibits intra-domain dynamics and a potential tendency to dimerize, which may expand its specifically targeted DNA sequence range. Our data provide a first molecular basis of and a starting point towards deciphering DNA- and RNA-binding functions of SAFB2 on the molecular level and serve a basis for understanding its localization to specific regions of chromatin and its involvement in the processing of specific RNA species. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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Review

Jump to: Research

21 pages, 10114 KiB

Open AccessReview

Virus Infection and mRNA Nuclear Export

by Jiayin Guo, Yaru Zhu, Xiaoya Ma, Guijun Shang, Bo Liu and Ke Zhang

Int. J. Mol. Sci. 2023, 24(16), 12593; https://doi.org/10.3390/ijms241612593 - 9 Aug 2023

Cited by 2 | Viewed by 1987

Abstract

Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for its translation into proteins. Along with transcription and translation, mRNA export through the nuclear pore complex (NPC) is an essential regulatory step in eukaryotic gene expression. Multiple factors regulate mRNA export and hence gene expression. Interestingly, proteins from certain types of viruses interact with these factors in infected cells, and such an interaction interferes with the mRNA export of the host cell in favor of viral RNA export. Thus, these viruses hijack the host mRNA nuclear export mechanism, leading to a reduction in host gene expression and the downregulation of immune/antiviral responses. On the other hand, the viral mRNAs successfully evade the host surveillance system and are efficiently exported from the nucleus to the cytoplasm for translation, which enables the continuation of the virus life cycle. Here, we present this review to summarize the mechanisms by which viruses suppress host mRNA nuclear export during infection, as well as the key strategies that viruses use to facilitate their mRNA nuclear export. These studies have revealed new potential antivirals that may be used to inhibit viral mRNA transport and enhance host mRNA nuclear export, thereby promoting host gene expression and immune responses. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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12 pages, 1623 KiB

Open AccessReview

Role of Proteostasis Regulation in the Turnover of Stress Granules

by Rirong Hu, Beituo Qian, Ang Li and Yanshan Fang

Int. J. Mol. Sci. 2022, 23(23), 14565; https://doi.org/10.3390/ijms232314565 - 23 Nov 2022

Cited by 4 | Viewed by 2536

Abstract

RNA-binding proteins (RBPs) and RNAs can form dynamic, liquid droplet-like cytoplasmic condensates, known as stress granules (SGs), in response to a variety of cellular stresses. This process is driven by liquid–liquid phase separation, mediated by multivalent interactions between RBPs and RNAs. The formation of SGs allows a temporary suspension of certain cellular activities such as translation of unnecessary proteins. Meanwhile, non-translating mRNAs may also be sequestered and stalled. Upon stress removal, SGs are disassembled to resume the suspended biological processes and restore the normal cell functions. Prolonged stress and disease-causal mutations in SG-associated RBPs can cause the formation of aberrant SGs and/or impair SG disassembly, consequently raising the risk of pathological protein aggregation. The machinery maintaining protein homeostasis (proteostasis) includes molecular chaperones and co-chaperones, the ubiquitin-proteasome system, autophagy, and other components, and participates in the regulation of SG metabolism. Recently, proteostasis has been identified as a major regulator of SG turnover. Here, we summarize new findings on the specific functions of the proteostasis machinery in regulating SG disassembly and clearance, discuss the pathological and clinical implications of SG turnover in neurodegenerative disorders, and point to the unresolved issues that warrant future exploration. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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22 pages, 36435 KiB

Open AccessReview

Conservation and Diversification of tRNA t⁶A-Modifying Enzymes across the Three Domains of Life

by Chenchen Su, Mengqi Jin and Wenhua Zhang

Int. J. Mol. Sci. 2022, 23(21), 13600; https://doi.org/10.3390/ijms232113600 - 6 Nov 2022

Cited by 11 | Viewed by 2169

Abstract

The universal N⁶-threonylcarbamoyladenosine (t⁶A) modification occurs at position 37 of tRNAs that decipher codons starting with adenosine. Mechanistically, t⁶A stabilizes structural configurations of the anticodon stem loop, promotes anticodon–codon pairing and safeguards the translational fidelity. The biosynthesis of tRNA t⁶A is co-catalyzed by two universally conserved protein families of TsaC/Sua5 (COG0009) and TsaD/Kae1/Qri7 (COG0533). Enzymatically, TsaC/Sua5 protein utilizes the substrates of L-threonine, HCO₃⁻/CO₂ and ATP to synthesize an intermediate L-threonylcarbamoyladenylate, of which the threonylcarbamoyl-moiety is subsequently transferred onto the A37 of substrate tRNAs by the TsaD–TsaB –TsaE complex in bacteria or by the KEOPS complex in archaea and eukaryotic cytoplasm, whereas Qri7/OSGEPL1 protein functions on its own in mitochondria. Depletion of tRNA t⁶A interferes with protein homeostasis and gravely affects the life of unicellular organisms and the fitness of higher eukaryotes. Pathogenic mutations of YRDC, OSGEPL1 and KEOPS are implicated in a number of human mitochondrial and neurological diseases, including autosomal recessive Galloway–Mowat syndrome. The molecular mechanisms underscoring both the biosynthesis and cellular roles of tRNA t⁶A are presently not well elucidated. This review summarizes current mechanistic understandings of the catalysis, regulation and disease implications of tRNA t⁶A-biosynthetic machineries of three kingdoms of life, with a special focus on delineating the structure–function relationship from perspectives of conservation and diversity. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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18 pages, 4760 KiB

Open AccessReview

Molecular Insights into mRNA Polyadenylation and Deadenylation

by Junjie Liu, Xubing Lu, Siyu Zhang, Ling Yuan and Yadong Sun

Int. J. Mol. Sci. 2022, 23(19), 10985; https://doi.org/10.3390/ijms231910985 - 20 Sep 2022

Cited by 3 | Viewed by 4947

Abstract

Poly(A) tails are present on almost all eukaryotic mRNAs, and play critical roles in mRNA stability, nuclear export, and translation efficiency. The biosynthesis and shortening of a poly(A) tail are regulated by large multiprotein complexes. However, the molecular mechanisms of these protein machineries still remain unclear. Recent studies regarding the structural and biochemical characteristics of those protein complexes have shed light on the potential mechanisms of polyadenylation and deadenylation. This review summarizes the recent structural studies on pre-mRNA 3′-end processing complexes that initiate the polyadenylation and discusses the similarities and differences between yeast and human machineries. Specifically, we highlight recent biochemical efforts in the reconstitution of the active human canonical pre-mRNA 3′-end processing systems, as well as the roles of RBBP6/Mpe1 in activating the entire machinery. We also describe how poly(A) tails are removed by the PAN2-PAN3 and CCR4-NOT deadenylation complexes and discuss the emerging role of the cytoplasmic poly(A)-binding protein (PABPC) in promoting deadenylation. Together, these recent discoveries show that the dynamic features of these machineries play important roles in regulating polyadenylation and deadenylation. Full article

(This article belongs to the Special Issue RNA-Binding Proteins — Structure, Function, Networks and Diseases)

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