The structural basis of SRSF6-mediated splicing decisions governed by tandem-domain RNA recognition and RS domain tuning
Year: 2026
Type: preprint
Abstract: Why and how cells exploit redundant versus complementary specificities of the 12 splice-regulatory SRSF(1–12) proteins remains enigmatic, but points at subtle details in their RNA binding modules. The resulting need in high-resolution information is especially evident for SRSF6 with no existing structures explaining its pre-mRNA selectivity. Using iCLIP, global splicing analyzes, RNA-Bind-and-Seq, integrated structural biology, molecular simulations, and systematic interaction studies including purified full-length eukaryotic protein, we provide the first atom-resolved basis of RNA-recognition by SRSF6 through RRM-, linker-, and RS-domains. SRSF6 uses its two differently typed RRMs in distinct interactions with constitutive (GAA-rich) or alternative exons (GGA) modulated by the RS domain, explaining previous inconsistencies within SRSF6-targeted motifs. Our findings suggest a mode of redundant and mutually exclusive splicing decisions between the closely related SRSF1 and SRSF6 as a blueprint for integrated splicing regulation by all 12 SRSF proteins.
Source: Research Square
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W7164852040