Response by Methawasin and Granzier to Letter Regarding Article, “Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function in a Mouse Model of Heart Failure With Preserved Ejection Fraction”

Methawasin, Mei; Granzier, Henk

doi:10.1161/circulationaha.117.026955

Cited by 1 publication

(1 citation statement)

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“…Mice strains that model abnormal titin stiffness show that crosses with Rbm20ΔRRM mice help promote a more compliant titin in the offspring with improvement of muscle function (Methawasin et al, 2014;Buck et al, 2014). Similarly, abnormal diastolic function in mouse models of heart failure with preserved ejection fraction (HFpEF) can be largely restored with heterozygous expression of Rbm20ΔRRM (Hinze et al, 2016;Bull et al, 2016;Methawasin et al, 2016). In both cases, it is likely that effects on additional targets related to cardiac performance may contribute to phenotypic changes in the Rbm20ΔRRM mice, notably splicing and expression levels of proteins involved in calcium sensitivity and contraction regulation (Pulcastro et al, 2016;Guo et al, 2018).…”

Section: In Terms Of Protein-protein Interactions Polypyrimidine Tramentioning

confidence: 99%

Structural basis of UCUU RNA motif recognition by splicing factor RBM20

Upadhyay

Mackereth

2019

Preprint

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The vertebrate splicing factor RBM20 (RNA Binding Motif protein 20) regulates protein isoforms important for heart development and function, with mutations in the gene linked to cardiomyopathy. Previous studies have identified the four base RNA motif UCUU as a common element in pre-mRNA targeted by RBM20. Here, we have determined the structure of the RNA Recognition Motif (RRM) domain from mouse RBM20 bound to RNA containing a UCUU sequence. The atomic details show that the RRM domain spans a larger region than initially proposed in order to interact with the complete UCUU motif, with a well-folded Cterminal helix encoded by exon 8 critical for high affinity binding. This helix only forms upon binding RNA with the final uracil, and removing the helix reduces affinity as well as specificity. We therefore find that RBM20 uses a coupled folding-binding mechanism by the C-terminal helix to specifically recognize the UCUU RNA motif.

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