8H9H

Crystal structure of ZBTB7A in complex with GACCC-containing sequence

Summary for 8H9H

• Entry DOI: 10.2210/pdb8h9h/pdb
• Descriptor: DNA (5'-D(*TP*AP*AP*GP*GP*AP*CP*CP*CP*AP*GP*AP*T)-3'), DNA (5'-D(P*AP*AP*TP*CP*TP*GP*GP*GP*TP*CP*CP*TP*T)-3'), Zinc finger and BTB domain-containing protein 7A, ... (5 entities in total)
• Functional Keywords: zbtb7a, primed to naive transition, transcription regulation, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 28445.67

Authors

Yang, Y. (deposition date: 2022-10-25, release date: 2023-04-26, Last modification date: 2023-11-29)

Primary citation

Yang, Y.,Xiao, L.,Xue, Y.,Idris, M.O.,Liu, J.,Pei, D.,Shi, Y.,Liao, B.,Li, F.
ZBTB7A regulates primed-to-naive transition of pluripotent stem cells via recognition of the PNT-associated sequence by zinc fingers 1-2 and recognition of gamma-globin -200 gene element by zinc fingers 1-4.
Febs J., 290:3896-3909, 2023

PubMed Abstract: ZBTB7A, a transcription factor containing a tandem array of four Cys2-His2 zinc fingers (ZFs), is vital for multiple physiological events through directional binding to different genomic loci. Our previously determined crystal structure of ZBTB7A in complex with a GCCCCTTCCCC sequence revealed that all four ZFs (ZF1-4) are involved in binding to γ-globin -200 gene element to repress fetal haemoglobin expression. Recently, it has been reported that ZBTB7A drives primed-to-naïve transition (PNT) of pluripotent stem cells through binding to a 12-bp consensus sequence ([AAGGACCCAGAT], referred to as PNT-associated sequence). Here, we report a crystal structure of ZBTB7A ZF1-3 in complex with the PNT-associated sequence. The structure shows that ZF1 and ZF2 primarily contribute to recognizing the GACCC core sequence mimicking the half part (GCCCC) of γ-globin -200 gene element via specific hydrogen bonding and van der Waals contacts. The mutations of key residues in ZF1-2 remarkably reduce their binding affinities for the PNT-associated sequence in vitro and cannot restore epiblast stem cells to the naïve pluripotent state in vivo. Collectively, our studies demonstrate that ZBTB7A mainly employs its ZF1-2 to recognize the PNT-associated sequence but recognizes γ-globin -200 gene element via ZF1-4, providing insights into the molecular mechanism for the diversity of ZBTB7A's genomic localization.

PubMed: 37013936
DOI: 10.1111/febs.16789

Experimental method

X-RAY DIFFRACTION (2.2 Å)