Double the Double: Revisiting <scp>BCL11B</scp>'s Multimerization

The transcription factor B Cell Lymphoma/Leukemia 11B (BCL11B) exerts a bi-directional function in cancer, with its role as an emerging therapeutic target in cancer treatment being particularly intriguing. BCL11B knockouts in cultured T cells revealed the acquisition of properties characteristic of natural killer cells, hinting at its importance in innate versus adaptive immune regulation. Our previous studies using Förster Resonance Energy Transfer-assisted Fluorescence-Activated Cell Sorting and Hybrid Solvent Replica-Exchange Simulations indicated that BCL11B forms dimers, with this being a prerequisite for its activity. However, size exclusion chromatography and crosslinking experiments have challenged this view, suggesting that BCL11B forms tetramers instead. An atypical CCHC zinc finger motif within the N-terminal region of the protein mediates multimerization and a novel 3D structure is presented based on extensive replica-exchange simulations in strong agreement with experimental data. The physiological relevance of multimer formation of this zinc finger protein has been demonstrated previously. Therefore, understanding the nature of BCL11B's multimerization could potentially enhance our ability to target this protein effectively, hopefully paving the way for novel BCL11B-targeted therapies.