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Cell. 2017 Jul 13;170(2):312-323.e10. doi: 10.1016/j.cell.2017.06.022.

Splicing Activation by Rbfox Requires Self-Aggregation through Its Tyrosine-Rich Domain.

Author information

1
Molecular Biology Interdepartmental Doctoral Program, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
2
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
3
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: dougb@microbio.ucla.edu.

Abstract

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:

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

PMID:
28708999
PMCID:
PMC5553710
DOI:
10.1016/j.cell.2017.06.022
[Indexed for MEDLINE]
Free PMC Article

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