Introduction to RNA Binding Proteins

What are RNA Binding Proteins?

RNA binding proteins form a large and diverse class of proteins that bind to RNA molecules to control their activity. RNA binding proteins are important for RNA splicing, transport, stability, translation and other cellular processes. The RBPs specifically recognize their RNA targets based on RBP's RNA-binding domains (RBDs) that recognize defined RNA nucleotide or structural moieties. RNA binding proteins form a large and diverse class of proteins that bind to RNA molecules to control their activity. RNA binding proteins are important for RNA splicing, transport, stability, translation and other cellular processes.

An example of protein-RNA hydrogen bonding interactions. (Corley, M.; et al, 2020)

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What are RNA-binding Domains?

Specific parts of a protein are termed as RNA-binding domains (RBDs) that help in binding of protein to RNA. These domains are required for the recognition and binding of distinct RNA sequences or structures, allowing the regulation of multiple aspects of RNA metabolism and function. RBDs have diverse specific RNA target proving this structure and composition is not fungible. Common RBDs include:

RNA Recognition Motif (RRM)

One of the most abundant RBDs, the RRM is characterized by its ability to bind single-stranded RNA through conserved aromatic residues.

KH Domain

Known for its role in binding single-stranded RNA, the KH domain interacts with RNA through a hydrophobic cleft, facilitating the stabilization of RNA-protein complexes.

Zinc Finger Domains

These domains bind to RNA through coordination with zinc ions, allowing for precise interactions with specific RNA sequences or structures.

DEAD-box Helicases Domain

These RBDs possess helicase activity, allowing them to unwind RNA secondary structures, a critical function for RNA processing and translation.

RNA-Binding Proteins Examples

RNA-binding proteins (RBPs) encompass a diverse array of proteins that interact with RNA molecules, influencing various aspects of RNA metabolism and function. Here are some examples and types of RBPs:

Heterogeneous Nuclear Ribonucleoproteins (hnRNPs)

These proteins are involved in RNA processing events such as splicing, mRNA export, and translation. hnRNPs contain RNA-binding domains like RRM and KH domains.

AU-Rich Element (ARE)-Binding Proteins

ARE-BPs regulate the stability and translation of mRNAs containing AU-rich elements in their 3' untranslated regions. Examples include HuR and TTP.

Serine/Arginine-Rich (SR) Proteins

SR proteins are essential splicing factors that bind to exonic splicing enhancers (ESEs) to promote exon inclusion during pre-mRNA splicing.

Double-Stranded RNA-Binding Proteins (DRBPs)

DRBPs, such as the RNA-dependent protein kinase (PKR) and Dicer, interact with double-stranded RNA molecules, participating in RNA interference (RNAi) and antiviral defense pathways.

Poly(A)-Binding Proteins (PABPs)

PABPs bind to the poly(A) tail of mRNAs, regulating mRNA stability, translation initiation, and mRNA export.

Staufen

Staufen is involved in mRNA transport and localization in neurons, binding to specific RNA sequences and facilitating their localization to dendrites.

Ribosomal Proteins

While ribosomal proteins are primarily known for their role in protein synthesis, some also possess RNA-binding activity and may influence ribosome assembly or translation efficiency.

Eukaryotic Initiation Factors (eIFs)

eIFs are involved in translation initiation and contain RNA-binding domains that recognize mRNA caps or other structural elements, facilitating ribosome recruitment and translation initiation.

Nucleolin

Nucleolin is a multifunctional protein involved in ribosome biogenesis, RNA processing, and regulation of gene expression. It interacts with various types of RNA, including rRNA and small noncoding RNAs.

Argonaute Proteins

Argonaute proteins are key components of the RNA-induced silencing complex (RISC) and play a central role in RNA interference (RNAi) and microRNA-mediated gene regulation.

How Does RNA Binding Proteins Impact Protein Synthesis?

RBPs significantly influence protein synthesis by modulating various stages of mRNA processing and translation. For example, eIF4E binding to the 5' cap structure of mRNAs is essential for the assembly of the eIF4F complex, which recruits the ribosomal machinery to initiate translation. Additionally, RBPs like IRP1 can inhibit translation by binding to IREs in the untranslated regions of mRNAs, thereby controlling the availability of mRNA for translation.

Regulation of Translation Initiation

RBPs can influence translation initiation by binding to specific sequences or structural elements within the mRNA. For example, eukaryotic initiation factors (eIFs), such as eIF4E, recognize the mRNA cap structure, promoting the recruitment of ribosomes to initiate translation. RBPs like eIF4E-binding proteins (4E-BPs) can regulate eIF4E activity, thus controlling translation initiation. Similarly, RBPs may bind to other regions of the mRNA, such as the 5' untranslated region (UTR) or internal ribosome entry sites (IRES), to modulate translation initiation efficiency.

mRNA Stability and Decay

RBPs can affect mRNA stability, thereby indirectly impacting protein synthesis. RBPs that bind to the 3' UTR of mRNAs, such as AU-rich element (ARE)-binding proteins like HuR and TTP, regulate mRNA stability by either stabilizing or promoting degradation of target transcripts. By controlling mRNA turnover rates, RBPs can regulate the availability of mRNAs for translation, influencing protein synthesis levels.

Alternative Splicing Regulation

RBPs involved in pre-mRNA splicing, such as serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), can influence the production of different mRNA isoforms encoding distinct protein variants. Alternative splicing events can result in the inclusion or exclusion of specific exons, leading to the generation of mRNA transcripts with altered coding sequences. Consequently, RBPs contribute to the diversification of the proteome by regulating the expression of alternative splice variants with unique protein functions.

mRNA Localization and Transport

Certain RBPs participate in mRNA localization and transport, ensuring that mRNAs are delivered to specific subcellular locations where they undergo translation. For instance, RBPs like Staufen are involved in the localization of mRNAs to dendrites in neurons, enabling localized protein synthesis at synapses. By regulating mRNA localization, RBPs contribute to spatially restricted protein synthesis, which is crucial for various cellular processes, including neuronal function and synaptic plasticity.

Modulation of RNA Structure and Accessibility

RBPs can remodel RNA secondary structures or influence RNA-protein interactions, thereby modulating the accessibility of mRNAs to the translation machinery. RNA helicases, for example, unwind RNA secondary structures to facilitate ribosome scanning and translation initiation. Additionally, RBPs may compete with each other for binding to specific RNA sequences, leading to differential effects on mRNA translation efficiency.

RNA Binding Proteins in Diseases

RBPs are key regulators of RNA metabolism, and their dysregulation is a common disease feature. RNA binding proteins (RBPs) play pivotal roles in gene regulation, and their dysfunction is linked to various diseases, such as neurodegenerative disorders, cancer, and other conditions. RBPs can form pathological aggregates (e.g., TDP-43 in ALS) or be sequestered by expanded RNA repeats (e.g., MBNL in myotonic dystrophy). Moreover, mutations can alter RBP binding or stability, while changes in RBP expression can disrupt mRNA metabolism. Besides, Dysregulation of splicing and mRNA stability by RBPs can produce abnormal protein isoforms or stabilize disease-promoting mRNAs.

Neurodegenerative Disorders

RBPs are crucial for neuronal function, and their malfunction can lead to neurodegeneration.

• Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD): Mutations in RBPs like TDP-43 and FUS are associated with ALS and FTD. These proteins typically regulate RNA processing, but mutations cause them to aggregate, disrupting cellular function and leading to neuronal death.
• Fragile X Syndrome: The loss of FMRP, an RBP, results in fragile X syndrome, the most common inherited intellectual disability. FMRP controls the translation of synaptic mRNAs, and its absence leads to excessive protein synthesis, affecting neurological function.

Cancer

RBPs influence mRNA metabolism critical for cancer development.

• HuR: This RBP stabilizes mRNAs of oncogenic proteins, promoting their expression. Overexpression of HuR is seen in many cancers and is linked to poor outcomes.
• Musashi-1: Frequently upregulated in cancers, Musashi-1 regulates mRNAs involved in cell cycle and apoptosis, promoting tumor growth and therapy resistance.

Myotonic Dystrophy

In this condition, expanded CUG or CCUG repeats in RNA sequester MBNL proteins, leading to widespread splicing defects and contributing to the disease's muscular and neurological symptoms.

Inflammatory Diseases

RBPs like tristetraprolin (TTP) regulate mRNAs encoding inflammatory cytokines. Dysfunction of TTP can lead to chronic inflammation, seen in conditions such as rheumatoid arthritis.

Hot Spot Research on RNA Binding Proteins

• RNA Binding Site Detection Technology
• Synthesis and Design of RNA Binding Proteins
• Role of RNA Binding Proteins in Stress Granules and Neurodegenerative Diseases
• Protein-RNA Interaction Assays

Reference

1. Corley, M.; et al. How RNA Binding Proteins Interact With RNA: Molecules And Mechanisms. Mol Cell. 2020, 78(1): 9–29.

Introduction to RNA Binding Proteins

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