title: Nuclear protein kinase CLK1 uses a non-traditional docking mechanism to select physiological substrates.
abstract: Phosphorylation-dependent cell communication requires enzymes that specifically recognize key proteins in a sea of similar, competing substrates. The protein kinases achieve this goal by utilizing docking grooves in the kinase domain or heterologous protein adaptors to reduce 'off pathway' targeting. We now provide evidence that the nuclear protein kinase CLK1 (cell division cycle2-like kinase 1) important for splicing regulation departs from these classic paradigms by using a novel self-association mechanism. The disordered N-terminus of CLK1 induces oligomerization, a necessary event for targeting its physiological substrates the SR protein (splicing factor containing a C-terminal RS domain) family of splicing factors. Increasing the CLK1 concentration enhances phosphorylation of the splicing regulator SRSF1 (SR protein splicing factor 1) compared with the general substrate myelin basic protein (MBP). In contrast, removal of the N-terminus or dilution of CLK1 induces monomer formation and reverses this specificity. CLK1 self-association also occurs in the nucleus, is induced by the N-terminus and is important for localization of the kinase in sub-nuclear compartments known as speckles. These findings present a new picture of substrate recognition for a protein kinase in which an intrinsically disordered domain is used to capture physiological targets with similar disordered domains in a large oligomeric complex while discriminating against non-physiological targets.
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
authors.forename: Malik M
authors.initials: MM
authors.lastname: Keshwani
authors.affiliation: Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Hailey
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Aubol
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fattet
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
authors.forename: Maria L
authors.initials: ML
authors.lastname: McGlone
authors.affiliation: Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, U.S.A. j2adams@ucsd.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Adams
mesh_terms: D002467:Cell Nucleus / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D004676:Myelin Basic Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004676:Myelin Basic Protein; D009687:Nuclear Proteins; C000595779:SRSF1 protein, human; D000068103:Serine-Arginine Splicing Factors; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases
keywords: docking; kinase; kinetics; oligomerization; phosphorylation; splicing