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Scientist (f/m) / PhD position Characterization and Structure Determination of Novel Protein Kinase Regulators involved in Cancer
Description:
Cell signaling is a key process in cell differentiation and oncogenesis. Protein kinases in particular play an eminent role in development, stem cells and cancer. Among protein kinases, the casein kinase 1 (CK1) family regulates Wnt signaling pathway at multiple levels. In this context, we have previously identified the DEAD-box RNA helicase DDX3 as a regulator of the Wnt-β-catenin network in embryonic development, where it acts as an allosteric activator of CK1. Moreover, both DDX3 and CK1 are oncogenes and hence their investigation is of relevance for the development of novel cancer therapeutics. The aim of this PhD project is to unravel the molecular mechanisms of the allosteric kinase-activation by an interdisciplinary approach including structure determination of the CK1-DDX3 complex. Thus, the project involves the production, purification, and structure determination by X-ray crystallography. This project is pursued in close collaboration between Prof. Dr. Irmgard Sinning and Prof. Dr. Christof Niehrs. The student will predominantly work in the lab of Prof. Sinning and will be exposed to/trained in a variety of approaches central to structural biochemistry and molecular cell biology.

References: Cruciat CM, Dolde C, de Groot RE, Ohkawara B, Reinhard C, Korswagen HC, Niehrs C. (2013) RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-β-catenin signaling. Science. 339:1436-41. Koch, S., Acebron, S.P., Herbst, J., Hatiboglu, G., and Niehrs, C. (2015) Posttranscriptional Wnt signaling governs epididymal sperm maturation. Cell 163:1225-36. Weyer, F. A., Gumiero, A., Valentín Gesé, G., Lapouge, K. and Sinning, I. (2017) Structural insights into a unique Hsp70/Hsp40 interaction in the eukaryotic ribosome-associated complex, Nat. Struct. Mol. Biol. 24:144-151. Grotwinkel, J.T., Wild, K., Segnitz, B. and Sinning, I. (2014) SRP RNA remodeling by SRP68 explains its role in protein translocation, Science 344: 101-104

Methods that will be used: Standard molecular biology methods, DNA transfection, protein expression in different cell types, Western blot analysis, luciferase reporter assays, protein kinase assays, high-end protein purification techniques, protein crystallization, advanced X-ray structure determination using synchrotron radiation sources, HDX-MS, thermophoresis, ITC, UV and CD spectroscopy.

Cooperation partners: Prof. Dr. Christof Niehrs (German Cancer Research Center)

 

Personal qualifications: Experience in biochemistry, cell or molecular biology

 

Deadline: 31. May 2017

 

Contact details: Sinning, Irmgard