Structural characterization of the protein kinase "target of rapamycin" and its interactions with regulators and substrates

• Applicant: Privatdozentin Dr. Sonja Alexandra Dames
• Subject Area: Structural Biology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 156863793

• Final Report Year: 2019

Final Report Abstract

Insgesamt hat die strukturbiologische Charakterisierung von selektierten Bereichen und deren direkten Lipid- und Membranwechselwirkungen der Kinase target of rapamycin (TOR) und zwei anderen Vertretern der Familie der Phosphatidylinositolkinase-verwandten Kinasen, ‘ataxia telangiectasia mutated’ (ATM) und ‘DNA protein kinase catalytic subunit’ (DNA-PKcs) ein besseres Verständnis der Lokalisierung an verschiedenen zellulären Membranen befördert. Die gewonnen Daten liefern nicht nur neue Einblicke in die Signalübermittlung an zellulären Membranen und die Rolle spezifischer Regulationsmechanismen für die hohe Zuverlässigkeit biochemischer Signalwege, sondern unterstützen auch das strukturbasierte Design neuer Wirkstoffe gegen Tuberkulose und PIKK-beeinflusste metabolische, neurodegenerative, Tumor- und Immunerkrankungen. Die FATC Domäne von TOR oder Teile davon wie auch die von ATM können Anwendung als Membrananker für andere Biomoleküle bzw. Wirkstoffe finden.

Publications

• Structural basis for the association of the redox-sensitive TOR FATC domain with membrane-mimetic DPC micelles, J Biol Chem. 2010; 285(10): 7766-75
  S.A. Dames
  
• 1H, 15N, and 13C assignments of the N-terminal activation domain of Dictyostelium discoideum Formin C, Biomol NMR Assign. 2011; 5(1):47-9
  S.A. Dames, A. Schönichen, and M. Geyer
  
• Characterization of the structure, dynamics, lipid-binding, and cellular localization of the N- terminal activation domain from Dictyostelium discoideum Formin C, J Biol Chem. 2011; 286(42): 36907-20
  S.A. Dames, A. Junemann, A. Schönichen, H. J. Sass, S. Grzesiek, J. Faix, and M. Geyer
  
• A fast and simple method for probing the interaction of peptides and proteins with lipids and membrane-mimetics by NMR using GB1 fusion proteins, Protein Sci. 2012; 21(10):1566-70
  Lisa A. M. Sommer, Sonja. A. Dames
  
• The FKBP-rapamycin binding domain of human TOR undergoes strong conformational changes in the presence of membranemimetics with and without the regulator phosphatidic acid, Biochemistry. 2012; 51(24):4909-21
  D. C. Rodriguez Camargo, N. M. Link, S. A. Dames
  
• NMR- and CD-Monitored Lipid-Binding Studies Suggest a General Role for the FATC Domain as Membrane Anchor of Phosphatidyl-Inositol-3 Kinase-Related Kinases (PIKKs), J Biol Chem. 2013; 288(27):20046-63
  Lisa A. M. Sommer, Martin Schaad, S. A. Dames
  
• Characterization of residue-dependent differences in the peripheral membrane association of the FATC domain of the kinase ‘target of rapamycin’ by NMR and CD spectroscopy, FEBS Lett. 2014; 588(9):1755-66
  Lisa A. M. Sommer, Sonja. A. Dames
  
• Characterization of the immersion properties of the peripheral membrane anchor of the FATC domain of the kinase ‘target of rapamycin’ by NMR, oriented CD spectroscopy and MD simulations, J Phys Chem B. 2014; 118(18):4817-31
  Lisa A. M. Sommer, D. Bennett, J. Janke, J. Bürck, A. S. Ulrich, P. Tieleman, Sonja. A. Dames
  
• Luc Brunsveld. Subtype-Specific Modulation of Estrogen Receptor–Coactivator Interaction by Phosphorylation, ACS Chem Biol. 2015; 10:475-484
  Inga M. Tharun, Lidia Nieto, Christian Haase, Marcel Scheepstra, Mark Balk, Sabine Möcklinghoff, Wencke Adriaens, Sonja A. Dames
  
• One cysteine rich sequence pattern – two different disulfide bonded structures – a molecular dynamics simulation study, J Pept Sci. 2015; 6:480-94
  Sonja A. Dames
  
• Regulation of the target of rapamycin and other phosphatidylinositol-3 kinase related kinases by membrane targeting, REVIEW, Membranes 2015; 5: 553-575
  Maristella De Cicco, Munirah S. Abd Rahim, Sonja A. Dames
  
• 1H, 15N, and 13C chemical shift assignments of the micelle immersed FAT C-terminal (FATC) domains of the human protein kinases ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) fused to the B1 domain of streptococcal protein G (GB1), Biomol NMR Assign. 2018 Apr;12(1):149-154
  Munirah S. Abd Rahim, Lisa A. M. Sommer, Anja Wacker, Sonja A. Dames
  
• NMR analysis of the backbone dynamics of the small GTPase Rheb and its interaction with the regulatory protein FKBP38., FEBS Lett. 2018; 1:130-146
  Maristella De Cicco, Leo Kiss, Sonja A. Dames
  
• Target of rapamycin FATC domain as a general membrane anchor: The FKBP-12 like domain of FKBP38 as a case study, Protein Sci. 2018; 2:546-560
  Maristella De Cicco, Lech G. Milroy, Sonja A. Dames
  
• NMR- and MD simulation-based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated, J Biol Chem. 2019 Mar 13
  Munirah S. Abd Rahim, Yevhen K. Cherniavskyi, D. Peter Tieleman, Sonja A. Dames