9E6T

BCL11A ZF4-6 in Complex with a DNA Sequence Observed in the Human Globin Locus Containing Motif TGCCCA

Summary for 9E6T

• Entry DOI: 10.2210/pdb9e6t/pdb
• Descriptor: B-cell lymphoma/leukemia 11A, DNA Strand I, DNA Strand II, ... (6 entities in total)
• Functional Keywords: transcription factor, dna binding, transcription, transcription-dna complex, globin locus, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 37381.87

Authors

Horton, J.R.,Cheng, X. (deposition date: 2024-10-30, release date: 2025-04-09, Last modification date: 2025-04-30)

Primary citation

Horton, J.R.,Yu, M.,Zhou, J.,Tran, M.,Anakal, R.R.,Lu, Y.,Blumenthal, R.M.,Zhang, X.,Huang, Y.,Zhang, X.,Cheng, X.
Multimeric transcription factor BCL11A utilizes two zinc-finger tandem arrays to bind clustered short sequence motifs.
Nat Commun, 16:3672-3672, 2025

PubMed Abstract: BCL11A, a transcription factor, is vital for hematopoiesis, including B and T cell maturation and the fetal-to-adult hemoglobin switch. Mutations in BCL11A are linked to neurodevelopmental disorders. BCL11A contains two DNA-binding zinc-finger arrays, low-affinity ZF2-3 and high-affinity ZF4-6, separated by a 300-amino-acid linker. ZF2-3 and ZF4-5 share 73% identity, including five out of six DNA base-interacting residues. These arrays bind similar short sequence motifs in clusters, with the linker enabling a broader binding span. Crystallographic structures of ZF4-6, in complex with oligonucleotides from the β-globin locus region, reveal DNA sequence recognition by residues Asn756 (ZF4), Lys784 and Arg787 (ZF5). A Lys784-to-Thr mutation, linked to a neurodevelopmental disorder with persistent fetal globin expression, reduces DNA binding over 10-fold but gains interaction with a variable base pair. BCL11A isoforms may form oligomers, enhancing chromatin occupancy and repressor functions by allowing multiple copies of both low- and high-affinity ZF arrays to bind DNA. These distinctive properties, apparently conserved among vertebrates, provide essential functional flexibility to this crucial regulator.

PubMed: 40246927
DOI: 10.1038/s41467-025-58998-7

Experimental method

X-RAY DIFFRACTION (2.78 Å)