Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1

Teplova, M.; Patel, Dinshaw J.

doi:10.1038/nsmb.1519

Cited by 147 publications

(241 citation statements)

References 40 publications

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“…In particular, the C-terminal ZnK2 masks the conserved aromatic residue (Y) at the fifth position of RNP1. Although these conserved ZnK motifs mask the putative RNA binding surface of the U2AF 23 , and by analogy, U2AF 35 UHMs, the ZnK family typically interacts with RNA (e.g., Hudson et al 2004;Teplova and Patel 2008). Approximately 10% of MDS-patients harbor acquired mutations of the U2AF1 gene that encodes the U2AF 35 splicing factor (for review, see Inoue et al 2016).…”

Section: Do Uhms Bind Rna?mentioning

confidence: 99%

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Loerch

Kielkopf

2016

RNA

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U2AF homology motifs (UHM) that recognize U2AF ligand motifs (ULM) are an emerging family of protein-protein interaction modules. UHM-ULM interactions recur in pre-mRNA splicing factors including U2AF1 and SF3b1, which are frequently mutated in myelodysplastic syndromes. The core topology of the UHM resembles an RNA recognition motif and is often mistakenly classified within this large family. Here, we unmask the charade and review recent discoveries of UHM-ULM modules for protein-protein interactions. Diverse polypeptide extensions and selective phosphorylation of UHM and ULM family members offer new molecular mechanisms for the assembly of specific partners in the early-stage spliceosome.

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Section: Do Uhms Bind Rna?mentioning

confidence: 99%

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Loerch

Kielkopf

2016

RNA

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“…The function of the ZnFs lies in the specific binding of GC dinucleotides contained in single-stranded RNA. 33,34 Edge et al 35 reported that MBNL1 is remarkably tolerant towards mutations in individual ZnFs, but mutations of ZnF1 and 2 are highly deleterious. The reported variant is known in public databases as rs185894411 with a minor allele frequency of 0.004%.…”

Section: Discussionmentioning

confidence: 99%

“…The variant described here is located between the second and third cysteine in a 3 10 -helix element. 33 In a 3D model of the first two ZnFs created with the SWISS-MODEL, 36 based on the known crystal structure of MBNL1 tandem ZF1 and 2 domain (PDB: 3D2N 33 ), the wild-type and variant containing p.(Thr32Met) were compared. Two alterations were visible: a shift in the shape of the protein due to the exchanged AA residue on protein position 32 and a change in the hydrophobicity of the region (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

et al. 2016

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The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG) n /(CCTG) n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBPassociated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) -associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.

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“…Binding of Muscleblind (Mbl) zinc finger domains to CUG repeats is strongly directed by the presence of aromatic residues (28). The sequence of the ABP1 hexapeptide is also enriched in aromatic amino acids.…”

Section: Abp1 Bound To Cug Repeats In Vitro Without Displacing Musclementioning

confidence: 99%

“…Interestingly, ABP1 has two aromatic amino acids in its sequence (tryptophan and tyrosine). The side chains of aromatic amino acids in a number of proteins have been found to be critical for enabling RNA binding, including the CCCH-type zinc finger protein Tis11, and MBNL1 (28,32).…”

Section: Abp1 Reversed Missplicing and Muscle Histopathology In A Dm1mentioning

confidence: 99%

In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

Garcia-Lopez

Llamusí

Orzáez

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Myotonic dystrophy type 1 (DM1) is caused by the expansion of noncoding CTG repeats in the dystrophia myotonica-protein kinase gene. Mutant transcripts form CUG hairpins that sequester RNAbinding factors into nuclear foci, including Muscleblind-like-1 protein (MBNL1), which regulate alternative splicing and gene expression. To identify molecules that target toxic CUG transcripts in vivo, we performed a positional scanning combinatorial peptide library screen using a Drosophila model of DM1. The screen identified a D-amino acid hexapeptide (ABP1) that reduced CUG foci formation and suppressed CUG-induced lethality and muscle degeneration when administered orally. Transgenic expression of natural, L-amino acid ABP1 analogues reduced CUG-induced toxicity in fly eyes and muscles. Furthermore, ABP1 reversed muscle histopathology and splicing misregulation of MBNL1 targets in DM1 model mice. In vitro, ABP1 bound to CUG hairpins and induced a switch to a single-stranded conformation. Our findings demonstrate that ABP1 shows antimyotonic dystrophy activity by targeting the core of CUG toxicity.disease model | drug discovery | non-coding RNA disease | medicinal chemistry | RNA secondary structure M yotonic dystrophy type 1 (DM1, OMIM #160900) is an autosomal dominant disease caused by the expansion of a CTG trinucleotide repeat in the 3′ untranslated region (UTR) of the dystrophia myotonica-protein kinase (DMPK) gene. Characteristic symptoms include myotonia, progressive muscle wasting, and cardiac conduction defects, among other systemic manifestations. The molecular mechanisms underlying DM1 pathogenesis are complex and affect a large number of cellular processes (1). However, most data suggest that the main triggering event is a toxic gain-of-function of the expanded CUG RNA. CUG-repeat expansions form double-stranded hairpins that are retained as inclusions within the nucleus. These hairpins recruit a number of transcription and splicing factors, including Muscleblind-like 1 (MBNL1) (2-6). Sequestration of MBNL1 originates a loss of function, which plays a key role in the development of DM1 symptoms. Mbnl1 knockout mice reproduced typical features of DM1, and overexpression of Mbnl1 in a mouse model that expressed CTG repeats reversed these phenotypes (7,8). CTGrepeat expression in mice caused misregulation of at least 156 alternative splicing events. Of these, 128 also occurred in Mbnl1 knockout animals (9-12). The splicing factor CUG-binding protein 1 (CUGBP1) is another key component in the development of DM1 phenotypes. CUGBP1 antagonizes MBNL1 activity in the regulated use of alternative exons in a number of transcripts and is abnormally upregulated in patients with DM1, further contributing to splicing misregulation (13-15).Mahadevan et al. provided the first in vivo proof-of-principle for a therapeutic strategy based on ablating toxic RNA molecules in DM1 (16). They demonstrated that expanded CTG-induced effects could be reverted if CTG-repeat transgene expression was interrupted in a DM1 mouse model. Several ...

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Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1

Cited by 147 publications

References 40 publications

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

In vivo discovery of a peptide that prevents CUG–RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models

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