Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations

Schulig, Lukas; Grabarczyk, Piotr; Geist, Norman; Delin, Martin; Forkel, Hannes; Kulke, Martin; Delcea, Mihaela; Schmidt, Christian A.; Link, Andreas

doi:10.3390/ijms22073650

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Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations

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Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, 17489 Greifswald, Germany

Department of Hematology and Oncology, Internal Medicine C, University Greifswald, 17489 Greifswald, Germany

Department of Biophysical Chemistry, Institute of Biochemistry, University of Greifswald, 17489 Greifswald, Germany

Author to whom correspondence should be addressed.

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These authors contributed equally to this work.

Academic Editors: Victor Muñoz and Stefano Gianni

Int. J. Mol. Sci. 2021, 22(7), 3650; https://doi.org/10.3390/ijms22073650

Received: 15 March 2021 / Revised: 29 March 2021 / Accepted: 30 March 2021 / Published: 31 March 2021

(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)

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Abstract

Transcription factors play a crucial role in regulating biological processes such as cell growth, differentiation, organ development and cellular signaling. Within this group, proteins equipped with zinc finger motifs (ZFs) represent the largest family of sequence-specific DNA-binding transcription regulators. Numerous studies have proven the fundamental role of BCL11B for a variety of tissues and organs such as central nervous system, T cells, skin, teeth, and mammary glands. In a previous work we identified a novel atypical zinc finger domain (CCHC-ZF) which serves as a dimerization interface of BCL11B. This domain and formation of the dimer were shown to be critically important for efficient regulation of the BCL11B target genes and could therefore represent a promising target for novel drug therapies. Here, we report the structural basis for BCL11B–BCL11B interaction mediated by the N-terminal ZF domain. By combining structure prediction algorithms, enhanced sampling molecular dynamics and fluorescence resonance energy transfer (FRET) approaches, we identified amino acid residues indispensable for the formation of the single ZF domain and directly involved in forming the dimer interface. These findings not only provide deep insight into how BCL11B acquires its active structure but also represent an important step towards rational design or selection of potential inhibitors. View Full-Text

Keywords: BCL11B; CCHC zinc finger; homodimerization; protein folding; protein-protein docking; replica-exchange molecular dynamics; TIGER2hs; TIGER2h

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Schulig, L.; Grabarczyk, P.; Geist, N.; Delin, M.; Forkel, H.; Kulke, M.; Delcea, M.; Schmidt, C.A.; Link, A. Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations. Int. J. Mol. Sci. 2021, 22, 3650. https://doi.org/10.3390/ijms22073650

AMA Style

Schulig L, Grabarczyk P, Geist N, Delin M, Forkel H, Kulke M, Delcea M, Schmidt CA, Link A. Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations. International Journal of Molecular Sciences. 2021; 22(7):3650. https://doi.org/10.3390/ijms22073650

Chicago/Turabian Style

Schulig, Lukas, Piotr Grabarczyk, Norman Geist, Martin Delin, Hannes Forkel, Martin Kulke, Mihaela Delcea, Christian A. Schmidt, and Andreas Link. 2021. "Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations" International Journal of Molecular Sciences 22, no. 7: 3650. https://doi.org/10.3390/ijms22073650

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Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations

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