Cell
Volume 170, Issue 2, 13 July 2017, Pages 312-323.e10
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Article
Splicing Activation by Rbfox Requires Self-Aggregation through Its Tyrosine-Rich Domain

https://doi.org/10.1016/j.cell.2017.06.022Get rights and content
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Highlights

  • The Rbfox C-terminal domain is sufficient to recruit LASR and is required for splicing

  • Higher-order Rbfox/LASR assembly requires repetitive tyrosine residues in the CTD

  • Rbfox aggregation, speckled localization, and splicing activation require tyrosines

  • Aggregation of RBPs plays a role in alternative splicing

Summary

Proteins of the Rbfox family act with a complex of proteins called the Large Assembly of Splicing Regulators (LASR). We find that Rbfox interacts with LASR via its C-terminal domain (CTD), and this domain is essential for its splicing activity. In addition to LASR recruitment, a low-complexity (LC) sequence within the CTD contains repeated tyrosines that mediate higher-order assembly of Rbfox/LASR and are required for splicing activation by Rbfox. This sequence spontaneously aggregates in solution to form fibrous structures and hydrogels, suggesting an assembly similar to the insoluble cellular inclusions formed by FUS and other proteins in neurologic disease. Unlike the pathological aggregates, we find that assembly of the Rbfox CTD plays an essential role in its normal splicing function. Rather than simple recruitment of individual regulators to a target exon, alternative splicing choices also depend on the higher-order assembly of these regulators within the nucleus.

Keywords

alternative splicing
RNA-binding protein
phase separation
posttranscriptional gene regulation
protein-protein interactions
protein aggregate

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