SR proteins are essential splicing factors that are regulated through multisite phosphorylation of their RS (arginine/serine-rich) domains by two major families of protein kinases. The SRPKs (SR-specific protein kinases) efficiently phosphorylate the arginine/serine dipeptides in the RS domain using a conserved docking groove in the kinase domain. In contrast, CLKs (Cdc2-like kinases) lack a docking groove and phosphorylate both arginine/serine and serine–proline dipeptides, modifications that generate a hyperphosphorylated state important for unique SR protein-dependent splicing activities. All CLKs contain long flexible N-terminal extensions (140–300 residues) that resemble the RS domains present in their substrate SR proteins. We showed that the N-terminus in CLK1 contacts both the kinase domain and the RS domain of the SR protein SRSF1 (SR protein splicing factor 1). This interaction not only is essential for facilitating hyperphosphorylation, but also induces co-operative binding of SRSF1 to RNA. The N-terminus of CLK1 enhances the total phosphoryl contents of a panel of physiological substrates including SRSF1, SRSF2, SRSF5 and Tra2β1 (transformer 2β1) by 2–3-fold. These findings suggest that CLK1-dependent hyperphosphorylation is the result of a general mechanism in which the N-terminus acts as a bridge connecting the kinase domain and the RS domain of the SR protein.
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Research Article|
July 24 2014
N-terminus of the protein kinase CLK1 induces SR protein hyperphosphorylation
Brandon E. Aubol;
Brandon E. Aubol
*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Ryan M. Plocinik;
Ryan M. Plocinik
*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Malik M. Keshwani;
Malik M. Keshwani
*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Maria L. McGlone;
Maria L. McGlone
*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Jonathan C. Hagopian;
Jonathan C. Hagopian
*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Gourisankar Ghosh;
Gourisankar Ghosh
†Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Xiang-Dong Fu;
Xiang-Dong Fu
‡Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
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Joseph A. Adams
Joseph A. Adams
1
*Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
1To whom correspondence should be addressed (email j2adams@ucsd.edu).
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Publisher: Portland Press Ltd
Received:
April 17 2014
Revision Received:
May 27 2014
Accepted:
May 29 2014
Accepted Manuscript online:
May 29 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 462 (1): 143–152.
Article history
Received:
April 17 2014
Revision Received:
May 27 2014
Accepted:
May 29 2014
Accepted Manuscript online:
May 29 2014
Citation
Brandon E. Aubol, Ryan M. Plocinik, Malik M. Keshwani, Maria L. McGlone, Jonathan C. Hagopian, Gourisankar Ghosh, Xiang-Dong Fu, Joseph A. Adams; N-terminus of the protein kinase CLK1 induces SR protein hyperphosphorylation. Biochem J 15 August 2014; 462 (1): 143–152. doi: https://doi.org/10.1042/BJ20140494
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