Molecular basis of RNA recognition by the human alternative splicing factor Fox-1
Open accessAbstract
The Fox-1 protein regulates alternative splicing of tissue-specific exons by binding to GCAUG elements. Here, we report the solution structure of the Fox-1 RNA binding domain (RBD) in complex with UGCAUGU. The last three nucleotides, UGU, are recognized in a canonical way by the four-stranded beta-sheet of the RBD. In contrast, the first four nucleotides, UGCA, are bound by two loops of the protein in an unprecedented manner. Nucleotides U1, G2, and C3 are wrapped around a single phenylalanine, while G2 and A4 form a base-pair. This novel RNA binding site is independent from the beta-sheet binding interface. Surface plasmon resonance analyses were used to quantify the energetic contributions of electrostatic and hydrogen bond interactions to complex formation and support our structural findings. These results demonstrate the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element.
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An NMR structure of the Rbfox1 RRM bound to UGCAUGU RNA shows G2 and G6 buried in two RRM pockets, stabilized by hydrogen bonds and stacking, and mutations at these positions produce the largest increases in binding free energy.
“examination of a previously determined NMR structure of the Rbfox1 RRM in complex with UGCAUGU RNA revealed that these two guanines are buried in two pockets of the RRM, and are stabilized by multiple hydrogen bonds and stacking interactions (Figure 2G); mutations in each of these two nucleotides resulted in the largest increases in the free energy of binding (Auweter et al., 2006).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Auweter et al., 2006
These crosslink sites probably reflect the residues in closest contact with the protein or those interacting with specific amino acids.
“We argue that these crosslink sites likely reflect the residues in closest contact with the protein or those interacting with specific amino acids, which agrees very well with a structure study of the protein-RNA complex (Auweter et al., 2006).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Auweter et al., 2006
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References 57 · Cited by 264
Research works printed but not linked: 4
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- Authors
- Auweter, S. D., Fasan, R., Reymond, L., Underwood, J. G., Black, D. L., Pitsch, S., & Allain, F. H.
- Affiliations
- ETH Zurich (CH)
- University of Zurich (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Allain, Frédéric H‐T
- Venue
- The EMBO Journal
- Published
- 2005-12-15
- Volume
- 25
- Issue
- 1
- Pages
- 163-173
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1356361
- OpenAlex
- W2102887078
- Cited by
- 264
- References
- 57
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 25 · 2023: 10 · 2022: 13 · 2021: 10 · 2020: 10 · 2019: 11 · 2018: 8 · 2017: 9 · 2016: 15 · 2015: 10 · 2014: 17 · 2013: 15 · 2012: 13
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Center of Competence in Research Chemical Biology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- alternative splicing, RNA recognition, RNA-binding domain, solution structure, sequence-specific RNA binding, protein-RNA complex, electrostatic interactions, hydrogen bonding, phenylalanine
- MeSH terms
- RNA Splicing Factors, Base Sequence, Humans, RNA, Messenger, RNA-Binding Proteins, Alternative Splicing, Protein Structure, Secondary, Protein Structure, Tertiary, Surface Plasmon Resonance
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