Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization
| Autor: | Shotaro Wani, Mai Iizuka, Yumiko Yamasaki-Kato, Marina Togo-Ohno, Matteo Vatta, Taeko Naruse, Katherine G. Spoonamore, Akinori Kimura, Tomohiko Ai, Yuichi Hiraoka, Richard J. Kovacs, Rie Murayama, Takeshi Yamamoto, Takeharu Hayashi, Masumi Saito, Mariko Kimura-Asami, Hidehito Kuroyanagi |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Cardiomyopathy Dilated Male 0301 basic medicine Adolescent RNA Splicing Nuclear Localization Signals Nonsense mutation Protein domain Mutation Missense lcsh:Medicine Mice Transgenic medicine.disease_cause Mice 03 medical and health sciences Protein Domains medicine Animals Humans Missense mutation Phosphorylation lcsh:Science Mutation Multidisciplinary biology Chemistry lcsh:R RNA-Binding Proteins Middle Aged Cell biology 030104 developmental biology Amino Acid Substitution RNA splicing biology.protein Female lcsh:Q Titin Nuclear localization sequence |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-14 (2018) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-26624-w |
| Popis: | RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20^ knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20^ mouse as a good model for in vivo study. 論文 |
| Databáze: | OpenAIRE |
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