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Biochem J. 2015 Mar 1;466(2):311-22. doi: 10.1042/BJ20141373.

Conserved proline-directed phosphorylation regulates SR protein conformation and splicing function.

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*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
†Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
‡Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.


The alternative splicing of human genes is dependent on SR proteins, a family of essential splicing factors whose name derives from a signature C-terminal domain rich in arginine-serine dipeptide repeats (RS domains). Although the SRPKs (SR-specific protein kinases) phosphorylate these repeats, RS domains also contain prolines with flanking serines that are phosphorylated by a second family of protein kinases known as the CLKs (Cdc2-like kinases). The role of specific serine-proline phosphorylation within the RS domain has been difficult to assign since CLKs also phosphorylate arginine-serine dipeptides and, thus, display overlapping residue specificities with the SRPKs. In the present study, we address the effects of discrete serine-proline phosphorylation on the conformation and cellular function of the SR protein SRSF1 (SR protein splicing factor 1). Using chemical tagging and dephosphorylation experiments, we show that modification of serine-proline dipeptides broadly amplifies the conformational ensemble of SRSF1. The induction of these new structural forms triggers SRSF1 mobilization in the nucleus and alters its binding mechanism to an exonic splicing enhancer in precursor mRNA. These physical events correlate with changes in the alternative splicing of over 100 human genes based on a global splicing assay. Overall, these studies draw a direct causal relationship between a specific type of chemical modification in an SR protein and the regulation of alternative gene splicing programmes.

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Conflict of interest statement

Author Contributions Malik Keshwani, Brandon Aubol, Chen-Ting Ma, and Jinsong Qui performed all the experiments in the study. Xiang-Dong Fu, Patricia Jennings, and Laurent Fattet participated in discussions and helped with data analysis. Joseph Adams and Malik Keshwani planned the experiments and wrote the paper.

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