Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/7/3650 |
| _version_ | 1797539356318105600 |
|---|---|
| author | Lukas Schulig Piotr Grabarczyk Norman Geist Martin Delin Hannes Forkel Martin Kulke Mihaela Delcea Christian A. Schmidt Andreas Link |
| author_facet | Lukas Schulig Piotr Grabarczyk Norman Geist Martin Delin Hannes Forkel Martin Kulke Mihaela Delcea Christian A. Schmidt Andreas Link |
| author_sort | Lukas Schulig |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T12:43:50Z |
| format | Article |
| id | doaj.art-c426d3ab945b4572bb341874a8fefb86 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:43:50Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c426d3ab945b4572bb341874a8fefb862023-11-21T13:40:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01227365010.3390/ijms22073650Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange SimulationsLukas Schulig0Piotr Grabarczyk1Norman Geist2Martin Delin3Hannes Forkel4Martin Kulke5Mihaela Delcea6Christian A. Schmidt7Andreas Link8Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, 17489 Greifswald, GermanyDepartment of Hematology and Oncology, Internal Medicine C, University Greifswald, 17489 Greifswald, GermanyDepartment of Biophysical Chemistry, Institute of Biochemistry, University of Greifswald, 17489 Greifswald, GermanyDepartment of Hematology and Oncology, Internal Medicine C, University Greifswald, 17489 Greifswald, GermanyDepartment of Hematology and Oncology, Internal Medicine C, University Greifswald, 17489 Greifswald, GermanyDepartment of Biophysical Chemistry, Institute of Biochemistry, University of Greifswald, 17489 Greifswald, GermanyDepartment of Biophysical Chemistry, Institute of Biochemistry, University of Greifswald, 17489 Greifswald, GermanyDepartment of Hematology and Oncology, Internal Medicine C, University Greifswald, 17489 Greifswald, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, 17489 Greifswald, GermanyTranscription 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.https://www.mdpi.com/1422-0067/22/7/3650BCL11BCCHC zinc fingerhomodimerizationprotein foldingprotein-protein dockingreplica-exchange molecular dynamics |
| spellingShingle | Lukas Schulig Piotr Grabarczyk Norman Geist Martin Delin Hannes Forkel Martin Kulke Mihaela Delcea Christian A. Schmidt Andreas Link Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations International Journal of Molecular Sciences BCL11B CCHC zinc finger homodimerization protein folding protein-protein docking replica-exchange molecular dynamics |
| title | Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations |
| title_full | Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations |
| title_fullStr | Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations |
| title_full_unstemmed | Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations |
| title_short | Unveiling the N-Terminal Homodimerization of BCL11B by Hybrid Solvent Replica-Exchange Simulations |
| title_sort | unveiling the n terminal homodimerization of bcl11b by hybrid solvent replica exchange simulations |
| topic | BCL11B CCHC zinc finger homodimerization protein folding protein-protein docking replica-exchange molecular dynamics |
| url | https://www.mdpi.com/1422-0067/22/7/3650 |
| work_keys_str_mv | AT lukasschulig unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT piotrgrabarczyk unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT normangeist unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT martindelin unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT hannesforkel unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT martinkulke unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT mihaeladelcea unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT christianaschmidt unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations AT andreaslink unveilingthenterminalhomodimerizationofbcl11bbyhybridsolventreplicaexchangesimulations |