title: Structural and Functional Analysis of the Cdk13/Cyclin K Complex.
abstract: Cyclin-dependent kinases regulate the cell cycle and transcription in higher eukaryotes. We have determined the crystal structure of the transcription kinase Cdk13 and its Cyclin K subunit at 2.0 Å resolution. Cdk13 contains a C-terminal extension helix composed of a polybasic cluster and a DCHEL motif that interacts with the bound ATP. Cdk13/CycK phosphorylates both Ser5 and Ser2 of the RNA polymerase II C-terminal domain (CTD) with a preference for Ser7 pre-phosphorylations at a C-terminal position. The peptidyl-prolyl isomerase Pin1 does not change the phosphorylation specificities of Cdk9, Cdk12, and Cdk13 but interacts with the phosphorylated CTD through its WW domain. Using recombinant proteins, we find that flavopiridol inhibits Cdk7 more potently than it does Cdk13. Gene expression changes after knockdown of Cdk13 or Cdk12 are markedly different, with enrichment of growth signaling pathways for Cdk13-dependent genes. Together, our results provide insights into the structure, function, and activity of human Cdk13/CycK.
authors.affiliation: Institute of Innate Immunity, Department of Structural Immunology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany; Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Ann Katrin
authors.initials: AK
authors.lastname: Greifenberg
authors.affiliation: Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; Max Planck Institute of Molecular Physiology, Department of Physical Biochemistry, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Hönig
authors.affiliation: Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Kveta
authors.initials: K
authors.lastname: Pilarova
authors.affiliation: Institute of Innate Immunity, Department of Structural Immunology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany; Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Düster
authors.affiliation: Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Koen
authors.initials: K
authors.lastname: Bartholomeeusen
authors.affiliation: Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; Max Planck Institute of Molecular Physiology, Department of Physical Biochemistry, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Bösken
authors.affiliation: Institute of Innate Immunity, Department of Structural Immunology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Anand
authors.affiliation: Central European Institute of Technology (CEITEC), Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Blazek
authors.affiliation: Institute of Innate Immunity, Department of Structural Immunology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany; Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany; Max Planck Institute of Molecular Physiology, Department of Physical Biochemistry, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany. Electronic address: geyer@uni-bonn.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
mesh_terms: D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D018844:Cyclin-Dependent Kinases
keywords: Cdk13; Cyclin K; Pin1; RNA polymerase II; flavopiridolIntroduction; transcription