RBM10: Structure, functions, and associated diseases

Abstract

RBM10 is a nuclear RNA-binding protein (RBP) that regulates the alternative splicing of primary transcripts. Recently, research on RBM10 has become increasingly active owing to its clinical importance, as indicated by studies on RBM0 mutations that cause TARP syndrome, an X-linked congenital pleiotropic developmental anomaly, and various cancers such as lung adenocarcinoma in adults. Herein, the molecular biology of RBM10 and its significance in medicine are reviewed, focusing on the gene and protein structures of RBM10, its cell biology, molecular functions and regulation, relationship with the paralogous protein RBM5, and the mutations of RBM10 and their associated diseases. Finally, the challenges in future studies of RBM10 are discussed in the concluding remarks.

Keywords: Alternative splicing; Antithetical effects of RBM10; RBM10 mutations and diseases; RBM5; Regulation of RBM10; Splicing network; X-inactivation.

Fig. 1.

Gene and Domain Structure of RBM10. (A) RBM10 gene structure (NCBI Reference Sequence: NG_012548.1). The RBM10 gene contains 24 exons, indicated by vertical closed boxes, with some of these numbered. Horizontal lines between exons indicate introns. Intron 2 is indicated with its relative length shortened by two-sevenths. (B) Schematic domain structure of RBM10. The structure of isoform 1 (930 aa residues) is shown. RBM10 has two RNA-binding domains in the N-terminal region: the RRM1-C4 ZnF di-domain and RRM2 domain. RBM10 isoforms 1 – 4 are determined by the inclusion or exclusion of the region encoded by exon 4 (box at residues 68–144) and of a Val residue at 354 (open triangle) (see also Fig. 3). The brackets at the bottom (residues 22–91 and 709–797) indicate the regions where phosphorylation occurs at multiple sites. K383 (closed triangle) undergoes acetylation/ubiquitylation. Note that the beginning and ending residue-numbers of the domains may not be strictly defined.

Fig. 2.

Domain structures of RBM10. (A) RNA recognition motifs (RRMs). (1) Schematic representation of a canonical RRM. RRM is composed of four β-sheets and two α-helices arranged in the order β1–α1–β2–β3–α2–β4. (2) 3D structure of RRM1. The figure schematically shows the RRM1 structure of RBM10 determined by NMR (Serrano et al., 2018; Protein Data Bank: 2LX1). The β3- and β1-strands containing RNP1 and RNP2 shown in panel (1) form an RNA-binding surface. (B and C) C₄ ZnF and C₂H₂ ZnF. The cysteine and histidine residues critical for the C₄- and C₂H₂-type ZnF structures and functions are highlighted in boldface. (D) OCRE (Octamer repeat). Brackets 1–5 represent five repeating octamers (8 aa) originally assigned based on hydrophilicity/hydrophobicity profiles (Inoue et al., 1996). The extended aa 564–618 forms a globular fold of 6 anti-parallel β-sheets (Martin et al., 2016). (E) NLS1. Basic aa residues in the bipartite sequence are highlighted. (F) KEKE region. Positive and negative aa residues characterizing the KEKE region are highlighted.

Fig. 3.

Transcript variants and protein isoforms of RBM10. Alternative splicing events in the primary transcript of RBM10 (A ~ C) generate mRNA variants v1–v5, which give rise to protein isoforms 1–5 (D). Exons, introns, and splice choices are illustrated using boxes, thick lines, and angled lines, respectively. The exons and introns are not shown to scale. Translation of v1–v4 and v5 starts from an initiation codon AUG (1) in exon 2 and an AUG codon (2) in exon 1, respectively. The isoforms have aliases (D), whose V354 and V277 correspond to the GTG (Val) codon at the end of exon 10 shown in C. The aliases in italic stand for their corresponding transcripts (not shown). The RefSeq numbers of each transcript and their protein isoforms as well as their sequences are found in the gene section of NCBI under RBM10.

Fig. 4.

Action model of RBM10. (A) AS events promoted by RBM10. RBM10 promotes skipping of target exons in substrate pre-mRNAs (1). In addition, it may promote other AS events (2) – (6), albeit less frequently. Exons, introns, and splice choices are illustrated using boxes, thick lines, and angled lines, respectively. (B) Association of RBM10 with the vicinity of the 3′-splice site (ss) of a target cassette exon in the spliceosome A complex. RBM10 brings about AS (skipping) of the cassette exon in association with the 35- and 65-kDa subunits of splicing factor U2AF and U2 snRNA of U2 snRNP. (C) Model of RBM10-mediated skipping of a cassette exon. RBM10 is believed to interfere with the 3′- and 5′-ss recognition and/or splice site pairing of the cassette exon, and to enhance the pairing of the distal 5′- and 3′-ss (in boldface). Exons, introns, and exon skipping by pairing of distal splice sites are indicated using boxes, thick horizontal lines, and an angled line, respectively.