Molecular basis of facilitated target search and sequence discrimination of TALE homeodomain transcription factor Meis1

Seo-Ree Choi, Juyong Lee (), Yeo-Jin Seo, Ho-Seong Jin, Hye-Bin Ahn, Youyeon Go, Nak-Kyoon Kim, Kyoung-Seok Ryu and Joon-Hwa Lee
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Seo-Ree Choi: Gyeongsang National University
Juyong Lee: Seoul National University
Yeo-Jin Seo: Gyeongsang National University
Ho-Seong Jin: Gyeongsang National University
Hye-Bin Ahn: Gyeongsang National University
Youyeon Go: Gyeongsang National University
Nak-Kyoon Kim: Korea Institute of Science and Technology
Kyoung-Seok Ryu: Korea Basic Science Institute
Joon-Hwa Lee: Gyeongsang National University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode). This study demonstrates that the non-specific binding mode of Meis1-HD is the energetically favored process during DNA binding, achieved by the interaction of the L1-α1 region with the phosphate backbone. An NMR dynamics study suggests that non-specific binding might set up an intermediate structure which can then rapidly and easily find the consensus region on a long section of genomic DNA in a facilitated binding process. Structural analysis using NMR and molecular dynamics shows that key structural distortions in the Meis1-HD–DNA complex are induced by various single nucleotide mutations in the consensus sequence, resulting in decreased DNA binding affinity. Collectively, our results elucidate the detailed molecular mechanism of how Meis1-HD recognizes single nucleotide mutations within its consensus sequence: (i) through the conformational features of the α3 helix; and (ii) by the dynamic features (rigid or flexible) of the L1 loop and the α3 helix. These findings enhance our understanding of how single nucleotide mutations in transcription factor consensus sequences lead to dysfunctional transcription and, ultimately, human disease.

Date: 2024
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DOI: 10.1038/s41467-024-51297-7

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