Evidence for cooperative tandem binding of hnRNP C RRMs in mRNA processing

Cieniková, Zuzana; Jayne, Sandrine; Damberger, Fred F.; Allain, Frédéric; Maris, Christophe

doi:10.1261/rna.052373.115

Cited by 31 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several experimental data proposed that multiple RRMs will help achieving higher affinity and specificity than the isolated RRM. 4,22 In this work, although the R38Q mutation does not directly act on the RNA-binding interface, some interfacial hydrogen bonds (Lys100-NZ:Cyt2-O2P and Met105-N:Cyt4-O2) are weakened because of the large fluctuations of RRM domains. Then, the calculated binding energy is increased in complex-R38Q system.…”

Section: Comparison Of Interactions In 3 Complex Systemsmentioning

confidence: 80%

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

Chang

Zhang

et al. 2016

RNA Biology

View full text Add to dashboard Cite

RNA-binding protein with multiple splicing (RBPMS) is critical for axon guidance, smooth muscle plasticity, and regulation of cancer cell proliferation and migration. Recently, different states of the RNA-recognition motif (RRM) of RBPMS, one in its free form and another in complex with CAC-containing RNA, were determined by Xray crystallography. In this article, the free RRM domain, its wild type complex and 2 mutant complex systems are studied by molecular dynamics (MD) simulations. Through comparison of free RRM domain and complex systems, it's found that the RNA binding facilitates stabilizing the RNA-binding interface of RRM domain, especially the C-terminal loop. Although both R38Q and T103A/K104A mutations reduce the binding affinity of RRM domain and RNA, the underlining mechanisms are different. Principal component analysis (PCA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods were used to explore the dynamical and recognition mechanisms of RRM domain and RNA. R38Q mutation is positioned on the homodimerization interface and mainly induces the large fluctuations of RRM domains. This mutation does not directly act on the RNA-binding interface, but some interfacial hydrogen bonds are weakened. In contrast, T103A/K104A mutations are located on the RNA-binding interface of RRM domain. These mutations obviously break most of high occupancy hydrogen bonds in the RNA-binding interface. Meanwhile, the key interfacial residues lose their favorable energy contributions upon RNA binding. The ranking of calculated binding energies in 3 complex systems is well consistent with that of experimental binding affinities. These results will be helpful in understanding the RNA recognition mechanisms of RRM domain.

show abstract

Section: Comparison Of Interactions In 3 Complex Systemsmentioning

confidence: 80%

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

Chang

Zhang

et al. 2016

RNA Biology

View full text Add to dashboard Cite

show abstract

“…Interestingly, Alu-exons with stable 3' splice site across primate species show an average U-tract length of 8–10 uridines (Figure 5A and B), which is at the lower limit of 9 to 10 uridines necessary to allow cooperative binding by the two RRMs of hnRNPC (Cieniková et al, 2015). We propose that a cryptic 3' splice site is best tolerated within an Alu element that already contains a long U-tract, while emergence of the same site in the absence of a long U-tract is subject to negative selection.…”

Section: Discussionmentioning

confidence: 99%

Splicing repression allows the gradual emergence of new Alu-exons in primate evolution

Attig

Mozos²,

Haberman³

et al. 2016

eLife

View full text Add to dashboard Cite

Alu elements are retrotransposons that frequently form new exons during primate evolution. Here, we assess the interplay of splicing repression by hnRNPC and nonsense-mediated mRNA decay (NMD) in the quality control and evolution of new Alu-exons. We identify 3100 new Alu-exons and show that NMD more efficiently recognises transcripts with Alu-exons compared to other exons with premature termination codons. However, some Alu-exons escape NMD, especially when an adjacent intron is retained, highlighting the importance of concerted repression by splicing and NMD. We show that evolutionary progression of 3' splice sites is coupled with longer repressive uridine tracts. Once the 3' splice site at ancient Alu-exons reaches a stable phase, splicing repression by hnRNPC decreases, but the exons generally remain sensitive to NMD. We conclude that repressive motifs are strongest next to cryptic exons and that gradual weakening of these motifs contributes to the evolutionary emergence of new alternative exons.DOI: http://dx.doi.org/10.7554/eLife.19545.001

show abstract

“…We have shown that the consensus RDE sequences are generally rich in multivalent binding sites for repressive RBPs. For instance, antisense Alus contain two separate U‐tracts that are often >8 nt long, and a U‐tract of 4 nts is sufficient to accommodate 1 RRM domain of hnRNPC . Thus, Alus with longer U‐tracts can accommodate multivalent binding of the four RRM domains of hnRNPC (two at each U‐tract), leading to high‐affinity binding.…”

Section: Exons Tend To Emerge From Rdes Through Gradual De‐repressionmentioning

confidence: 97%

Genomic Accumulation of Retrotransposons Was Facilitated by Repressive RNA‐Binding Proteins: A Hypothesis

Attig

Ule

2019

BioEssays

View full text Add to dashboard Cite

Retrotransposon‐derived elements (RDEs) can disrupt gene expression, but are nevertheless widespread in metazoan genomes. This review presents a hypothesis that repressive RNA‐binding proteins (RBPs) facilitate the large‐scale accumulation of RDEs. Many RBPs bind RDEs in pre‐mRNAs to repress the effects of RDEs on RNA processing, or the formation of inverted repeat RNA structures. RDE‐binding RBPs often assemble on extended, multivalent binding sites across the RDE, which ensures repression of cryptic splice or polyA sites. RBPs thereby minimize the effects of RDEs on gene expression, which likely reduces the negative selection against RDEs. While mutations that change splice sites in RDEs act as an off‐on switch in exon formation, mutations that decrease the multivalency of RBP binding sites resemble a rheostat that enables a more gradual evolution of new RDE‐derived exons. RBPs might also repress aberrant processing of active retrotransposons, thus increasing the chance that full‐length copies are made. Taken together, in this review, it is proposed that RBPs facilitate the widespread accumulation of intronic RDEs by repressing RNA processing while chaperoning their potential to gradually evolve into new exons.

show abstract

Evidence for cooperative tandem binding of hnRNP C RRMs in mRNA processing

Cited by 31 publications

References 53 publications

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

Splicing repression allows the gradual emergence of new Alu-exons in primate evolution

Genomic Accumulation of Retrotransposons Was Facilitated by Repressive RNA‐Binding Proteins: A Hypothesis

Contact Info

Product

Resources

About