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11
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RNA–Protein Interactions: A New Approach for Drugging
RNA Biology
Dalia M. Soueid and Amanda L. Garner
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor,
Michigan 48109, USA
One of the many mechanisms by which RNAs are regulated in the cell is through
interactions with RNA-binding proteins (RBPs). Indeed, the extent to which the cell
utilizes RBP-mediated RNA regulation is astonishing. RBPs have classically been
dened by the presence of one or more RNA-binding domain (RBD), which are
capable of recognizing specic sequences and/or structural motifs on an RNA [1–6].
Preliminary analyses using sequence alignment of known RBPs and computational
prediction to map various RBDs across organisms led to the uncovering of ∼500
RBPs in mice and ∼700 in humans [7–9]. With the advent of large-scale sequencing technologies, these lists continue to grow. It is now estimated that there are over
2000 RBPs in humans, many of which do not contain canonical RBDs, redening our
perception of RBPs and their roles in regulating cellular RNA biology [10]. These
discoveries were catalyzed by an explosion in the development of new methods,
providing novel insights into the regulation of RNA biology, including RNA-centric
and protein-centric approaches which enable mapping RNA–protein interactions
(RPIs) across the transcriptome [11, 12]. As numerous RBP-recognition motifs can
exist within a single RNA molecule, RNAs are often invariably bound and regulated
by multiple RBPs, resulting in the formation of complex and dynamic ribonucleoprotein complexes (RNPs). These complexes play fundamental roles in controlling
nearly all aspects of gene expression from splicing to translation, modulating RNAs
throughout their entire lifecycle from birth (i.e. transcription) to death (i.e. degradation) [13]. Accordingly, dysregulation of the networking between RNAs and RBPs
has been shown to lead to a number of human diseases, including neurodegenerative
disorders and cancers. This connection between RBP biology and disease, in turn,
has catalyzed an interest in drugging RPIs. Herein, we will discuss the molecular
basis for RPIs and highlight the signicance of RPIs including several well-validated
examples in which dysregulation of these interactions could be the basis for disease.
We will then summarize experimental methods developed to detect these interactions with the purpose of promoting drug discovery eorts.
281
RNA as a Drug Target: The Next Frontier for Medicinal Chemistry, First Edition.
Edited by John Schneekloth and Martin Pettersson.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
282 11 RNA–Protein Interactions: A New Approach for Drugging RNA Biology
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11.1 Molecular Basis of RNA–Protein Interactions
RBPs have traditionally been dened by the presence of one or more canonical RBDs
[1], such as RNA recognition motifs (RRMs) [14], double-stranded RBDs [15], zinc
ngers [16], and K homology domains among others [17]. While RBPs often contain
multiple copies of the same type of RBD, they can also contain a combination of distinct RBDs that direct their binding to diverse RNA motifs. RBDs are typically <100
amino acids, and only a small portion of the domain is responsible for interacting
with an RNA [18]. As such, the binding footprint for an RBD on an RNA is only 6–8
nucleotides in length [19]. RBPs gain specicity by binding to multiple RNA motifs
within a single substrate. Intrinsically disordered regions and linkers are also characteristic of many RBPs, which enable these proteins to engage in multivalent binding
to an RNA [20]. Other levels of RBP regulation include posttranslational modications and protein–protein interactions (PPIs) [21, 22]. The combination of all these
elements in the protein, in addition to abundance, localization, and RNA-binding
site arrangement within the secondary structure of an RNA substrate, contributes to
the specicity observed for select RPIs. Later, we will highlight key RBDs and discuss their modes of molecular recognition of an RNA. A summary of examples of
RBPs that utilize these domains, as well as their biological functions, can be found
in Table 11.1.
11.1.1 RNA Recognition Motifs (RRMs)
RRMs, also referred to as RNP domains, are not only the most abundant protein
domains found in RBPs but they are also one of the most abundant protein
domains found in eukaryotes [41, 42]. RRM-containing proteins play a functional
role in a majority of posttranscriptional gene regulation including mRNA and
rRNA processing, RNA nuclear export, and RNA stability [13]. In addition to
interacting with RNAs, RRMs also interact with DNA and facilitate PPIs [14].
This commonly occurring protein domain consists of roughly 90 amino acids
with two conserved central sequences termed RNP1 (8 bases) and RNP2 (6 bases),
which are responsible for RNA binding [43]. These conserved sequences contain primarily aromatic and positively charged amino acids and are dened by
the following sequences: RNP1 – [RK]-G-[*FY]-[GA]-[*FY]-[ILV]-X-[FY] and
RNP2 – [ILV]-[*FY]-[ILV]-X-N-L, where “X” is any amino acid and “*” denotes the
aromatic residue which interacts directly with RNA [44, 45].
While RRMs have been shown to bind to virtually all single-stranded RNA
sequences in vitro [14], structural studies have demonstrated how dierent RRMs
achieve binding specicity for unique RNA sequences. Despite having similar
folds, each RRM-containing RBP or individual RRMs within a protein containing
multiple RRMs, exhibit varied specicities and binding anities for certain RNA
sequences [46, 47]. The typical fold of an RRM consists of four β-sheets packed
against two α-helices in the arrangement β1α1β2β3α2β4(Figure 11.1) [41]. The β
and β3strands make up the primary RNA binding surface, driven primarily by
three aromatic residues in RNP1 and RNP2 where two of the residues stack with
1
Table 11.1 Representative examples of RBPs and RBP families harboring various RBDs and their broad cellular functions.
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RBDs RBPs/Families Main function
RRM Musashi Regulate mRNA translation in neural development and maintenance of adult neural stem cells [23]
hnRNPs Broadly involved in nucleic acid metabolism: splicing, mRNA stabilization, transcriptional/translational regulation [24]
SR Proteins (contain
RG domains)
Hu Antigen Proteins HuB, HuC, and HuD function in neuronal dierentiation and plasticity; HuR mostly functions in cellular stress
dsRBD Staufen Mainly important for RNA localization, also play conserved roles in early dierentiation of neurons and plasticity of
Dicer Riboendonuclease that functions as a critical regulator of the biogenesis of small RNAs, including microRNAs, small
TARBP Various roles in innate immune response and cellular stress response; integral part of the RNA-induced silencing
ZnF Mbnl Important regulators of tissue-specic alternative splicing that have a key role in terminal muscle dierentiation;
TTP Regulates translation (via degradation or repression) of proinammatory cytokines by binding to mRNA [32]
Roquin & Regnase Important roles in the prevention of inammatory and autoimmune diseases through inducing
Splice site recognition and major players in recruitment and stabilization of components of the core spliceosome [25]
response [26]
mature neurons [27]
interfering RNAs, and small nucleolar RNAs [28, 29]
complex with Dicer and Argonaute proteins [30]
transcript-dependent activators or repressors of splicing [31]
degradation/translational repression of target mRNAs relevant to T cell dierentiation [33]
(Continued)
Table 11.1 (Continued)
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RBDs RBPs/Families Main function
KH STAR Signal transducer and activator of RNA which binds to mRNA targets and regulates processes such as cell cycle and
FUBP Broad functions in RNA processing including mRNA splicing, stability, export, and translation and also exhibit
Vigilin Evolutionarily conserved family of proteins containing tandem KH domains, which perform numerous cellular
NusA, NusB, NusE,
NusG
CSD Lin28 Protein, which is expressed at dierent developmental stages of various tissues and organs, plays important functions as
YTH YTHDF & YTHDC
family
PUF Pumilio and FBF
(PUF) Family
tissue development [34]
transcriptional control through binding to ssDNA sequences [35]
functions including mRNA stabilization, translational regulation, stress granule component, tRNA shuttling, P-body
regulation, and heterochromatin regulation [36]
Regulate dierent phases of initiation, elongation, and termination of bacterial transcription through interactions with
bacterial RNA polymerase and RNA [37]
a cell division activator and inhibitor of dierentiation, and interacts with both pre-miRNAs and mRNAs [38]
Function as essential readers of m6A modications, playing important regulatory roles in almost all stages of methylated
RNA metabolism and are involved in the development and progression of many tumors [39]
Highly conserved eukaryotic RBPs which interact with regulatory elements in the 3′UTR of mRNA targets to promote
RNA decay and translational repression and also promote ribosome stalling, recruitment of miRNAs, and chromosomal
instability [40]
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