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Ndr/Lats Kinases Bind Specific Mob-Family Coactivators through a Conserved and Modular Interface.
Parker, Benjamin W; Gogl, Gergo; Bálint, Mónika; Hetényi, Csaba; Reményi, Attila; Weiss, Eric L.
Afiliação
  • Parker BW; Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Gogl G; Institute of Organic Chemistry, Research Center for Natural Sciences, Magyar Tudósok körútja, 1117 Budapest, Hungary.
  • Bálint M; Equipe Labellisee Ligue 2015, Department of Integrated Structural Biology, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U1258/CNRS UMR 7104/Universite de Strasbourg, 1 rue Laurent Fries, BP 10142, F-67404 Illkirch, France.
  • Hetényi C; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
  • Reményi A; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
  • Weiss EL; Institute of Organic Chemistry, Research Center for Natural Sciences, Magyar Tudósok körútja, 1117 Budapest, Hungary.
Biochemistry ; 59(17): 1688-1700, 2020 05 05.
Article em En | MEDLINE | ID: mdl-32250593
Ndr/Lats kinases bind Mob coactivator proteins to form complexes that are essential and evolutionarily conserved components of "Hippo" signaling pathways, which control cell proliferation and morphogenesis in eukaryotes. All Ndr/Lats kinases have a characteristic N-terminal regulatory (NTR) region that binds a specific Mob cofactor: Lats kinases associate with Mob1 proteins, and Ndr kinases associate with Mob2 proteins. To better understand the significance of the association of Mob protein with Ndr/Lats kinases and selective binding of Ndr and Lats to distinct Mob cofactors, we determined crystal structures of Saccharomyces cerevisiae Cbk1NTR-Mob2 and Dbf2NTR-Mob1 and experimentally assessed determinants of Mob cofactor binding and specificity. This allowed a significant improvement in the previously determined structure of Cbk1 kinase bound to Mob2, presently the only crystallographic model of a full length Ndr/Lats kinase complexed with a Mob cofactor. Our analysis indicates that the Ndr/LatsNTR-Mob interface provides a distinctive kinase regulation mechanism, in which the Mob cofactor organizes the Ndr/Lats NTR to interact with the AGC kinase C-terminal hydrophobic motif (HM), which is involved in allosteric regulation. The Mob-organized NTR appears to mediate association of the HM with an allosteric site on the N-terminal kinase lobe. We also found that Cbk1 and Dbf2 associated specifically with Mob2 and Mob1, respectively. Alteration of residues in the Cbk1 NTR allows association of the noncognate Mob cofactor, indicating that cofactor specificity is restricted by discrete sites rather than being broadly distributed. Overall, our analysis provides a new picture of the functional role of Mob association and indicates that the Ndr/LatsNTR-Mob interface is largely a common structural platform that mediates kinase-cofactor binding.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Sequência Conservada / Proteínas de Saccharomyces cerevisiae / Peptídeos e Proteínas de Sinalização Intracelular / Proteínas do Tecido Nervoso Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Sequência Conservada / Proteínas de Saccharomyces cerevisiae / Peptídeos e Proteínas de Sinalização Intracelular / Proteínas do Tecido Nervoso Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article