Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 30, Pages E2802-E2811Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303445110
Keywords
NMR; protein-RNA complex; splicing factor
Categories
Funding
- Schweizerischer National-fonds-National Centers of Competence in Research Structural Biology
- European Alternative Splicing Network (EURASNET)
- EURASNET
- Consolider RNAREG
- Fundacion Marcelino Botin
- European Molecular Biology Organization
- Fondation Suisse de Recherche sur les Maladies Musculaires
- National Institutes of Health [R37-GM42699]
- ICREA Funding Source: Custom
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Serine/arginine (SR) proteins, one of the major families of alternative-splicing regulators in Eukarya, have two types of RNA-recognition motifs (RRMs): a canonical RRM and a pseudo-RRM. Although pseudo-RRMs are crucial for activity of SR proteins, their mode of action was unknown. By solving the structure of the human SRSF1 pseudo-RRM bound to RNA, we discovered a very unusual and sequence-specific RNA-binding mode that is centered on one alpha-helix and does not involve the beta-sheet surface, which typically mediates RNA binding by RRMs. Remarkably, this mode of binding is conserved in all pseudo-RRMs tested. Furthermore, the isolated pseudo-RRM is sufficient to regulate splicing of about half of the SRSF1 target genes tested, and the bound alpha-helix is a pivotal element for this function. Our results strongly suggest that SR proteins with a pseudo-RRM frequently regulate splicing by competing with, rather than recruiting, spliceosome components, using solely this unusual RRM.
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