The RNA recognition motif, a plastic RNA‐binding platform to regulate post‐transcriptional gene expression

Abstract

The RNA recognition motif (RRM), also known as the RNA-binding domain (RBD) or ribonucleoprotein domain (RNP), was first identified in the late 1980s when it was demonstrated that mRNA precursors (pre-mRNA) and heterogeneous nuclear RNAs (hnRNAs) are always found in complex with proteins (reviewed in [1]). Biochemical characterizations of the mRNA polyadenylate binding protein (PABP) and the hnRNP protein C shed light on a consensus RNA-binding domain of approximately 90 amino acids containing a central sequence of eight conserved residues that are mainly aromatic and positively charged [2,3]. This sequence, termed the RNP consensus sequence, was thought to be involved in RNA interaction and was defined as Lys ⁄ ArgGly-Phe ⁄ Tyr-Gly ⁄ Ala-Phe ⁄ Tyr-Val ⁄ Ile ⁄ Leu-X-Phe ⁄ Tyr, where X can be any amino acid. Later, a second consensus sequence less conserved than the previously characterized one [1] The RNA recognition motif (RRM), also known as RNA-binding domain (RBD) or ribonucleoprotein domain (RNP) is one of the most abundant protein domains in eukaryotes. Based on the comparison of more than 40 structures including 15 complexes (RRM-RNA or RRM-protein), we reviewed the structure-function relationships of this domain. We identified and classified the different structural elements of the RRM that are important for binding a multitude of RNA sequences and proteins. Common structural aspects were extracted that allowed us to define a structural leitmotif of the RRM-nucleic acid interface with its variations. Outside of the two conserved RNP motifs that lie in the center of the RRM b-sheet, the two external b-strands, the loops, the C-and N-termini, or even a second RRM domain allow high RNA-binding affinity and specific recognition. Protein-RRM interactions that have been found in several structures reinforce the notion of an extreme structural versatility of this domain supporting the numerous biological functions of the RRM-containing proteins.Abbreviations ACF, APOBEC-1 complementary factor; CBP, cap binding protein; CstF, cleavage stimulation factor; hnRNP, heterogeneous nuclear ribonucleoprotein; HuD, Hu protein D; LRR, leucine rich repeat; MIF4G, middle domain of the translation initiation factor 4 G; PABP, polyadenylate binding protein; PIE, polyadenylation inhibition element; PTB, polypyrimidine tract binding protein; RBD, RNA-binding domain; RNP, ribonucleoprotein; RRM, RNA recognition motif; SR, serine/arginine rich proteins; TLS, translocated in liposarcoma; U1A, U2A¢, U2B¢: U1 snRNP proteins A, A¢, B¢; U2AF, U2 snRNP auxiliary factor; UHM, U2AF homology motif; UPF, up-frameshift protein.

The human RBPome: From genes and proteins to human disease

“…The domain distribution of this catalogue ( Figure 1B) illustrates the presence of various known and well-studied RNA binding domains like RRM (RNA recognition motif) [30], K-homology (KH) [31,32], DEAD/DEAH box [33], dsrm [34], WD40 [35] in addition to unclassified domains like the Pkinase domain of EIF2AK2 that auto phosphorylates upon binding of RNA to the dsRBD domain of EIF2AK2 [36,37]. Also notable is the Calponin homology (CH) domain found in both cytoskeletal and signalling proteins [38].…”

Regulatory elements involved in the post-transcriptional control of stage-specific gene expression in Trypanosoma cruzi: a review

“…The RRM domain can bind to cisacting elements ranging from two-eight nucleotides in length, and proteins with this domain exhibit a large range of affinities and specificities. RRMs are found in proteins involved in various post-transcriptional events, such as RNA processing, transport, translation, degradation and stability (Maris et al 2005). However, few RRM-containing proteins have been characterised in T. cruzi.…”

Prediction of a new class of RNA recognition motif

“…The RNA Recognition Motif (RRM) is one of the most abundant in eukaryotes, and is estimated to be present in 2% of the human gene products [35]. Initial biochemical studies on poly(A)-binding protein (PABP) and hnRNP protein C defined a consensus RNA-binding domain of about 90 residues containing a central sequence of eight conserved residues [36,37].…”

“…Although just three residues out of eight are strictly conserved, it could be sequences, and also an equivalent Asp is found in the ALY RNP1 sequence [35]. Finally, the residue at position 8 is not conserved, as is the case of the polypyrimidine-tract-binding protein (PTB) RNP1 sequences A and C, the Nucleolin RNP1 sequence B, the LA and the 13 PABP sequences [35]. Taking all of these criteria into account, the sequence of RNP1 of ADA4h approaches the consensus except for the lack of Gly in position 2.…”