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BP: Fachverband Biologische Physik
BP 31: Protein Structure and Dynamics
BP 31.1: Talk
Thursday, March 21, 2024, 15:00–15:15, H 0112
BCL11B CCHC Zinc Finger Domain and Its Potential for Cancer Therapy — •Anne Susemihl1,3, Lukas Schulig2, Norman Geist1, Piotr Grabarczyk3, Felix Nagel1, Christian Andreas Schmidt3, and Mihaela Delcea1 — 1Institute of Biochemistry, Greifswald, Germany — 2Institute of Pharmacy, Greifswald, Germany — 3University Medicine, Greifswald, Germany
B Cell Lymphoma/Leukemia 11B (BCL11B) is a transcription factor, exerting a bi-directional role in cancer. BCL11B KO in vitro lead to T cells acquiring properties of natural killer cells, suggesting BCL11B*s role as an emerging cancer target. Previous FACS-FRET experiments and extensive enhanced sampling simulations indicated that BCL11B forms dimers, with this being a prerequisite for its functionality. New simulations and size exclusion chromatography data suggest the formation of not only dimers but tetramers. Multimerization is mediated by an atypical CCHC zinc finger (ZF) motif within the N-terminal region of the protein. Understanding the nature of BCL11B*s multimerization and its zinc binding properties may enable the use of BCL11B in targeted cancer therapy. We show here that zinc coordination is essential for the oligomerization of the N-terminal domain. Zinc binding properties of the CCHC ZF domain were determined using UV-Vis spectroscopy and isothermal titration calorimetry. BCL11B mutations within the tetramer interface led to insufficient zinc binding and incomplete ZF formation, resulting in monomerization. Other mutants showed monomerization but tetramer formation with the wild type zinc finger, with the physiological relevance yet to be elucidated.
Keywords: BCL11B; multimerization; zinc finger protein; mutations