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경상국립대학교, 한국과학기술연구원

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Nat. Commun., Aug 14 2024, 15 (1) | https://doi.org/10.1038/s41467-024-51297-7 Molecular basis of facilitated target search and sequence discrimination of TALE homeodomain transcription factor Meis1

Seo-Ree Choi^1,2,7, Juyong Lee^3,4,5,7, Yeo-Jin Seo¹, Ho-Seong Jin¹, Hye-Bin Ahn¹, Youyeon Go¹, Nak-Kyoon Kim², Kyoung-Seok Ryu⁶ & Joon-Hwa Lee^1,8

¹Department of Chemistry and RINS, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea.

²Advanced Analysis Data Center, Korea Institute of Science and Technology, Seoul 02456, Republic of Korea.

³Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

⁴Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

⁵Arontier Co., Seoul 06735, Republic of Korea.

⁶Protein Structure Research Team, Korea Basic Science Institute, Cheongju, Chungcheongbuk-do 28119, Republic of Korea.

⁷These authors contributed equally: Seo-Ree Choi, Juyong Lee.

⁸Deceased: Joon-Hwa Lee

Corresponding author

Correspondence to Juyong Lee.

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.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-16)
연구진국내 연구진
분야 생명과학 > 구조생물 및 생물물리학

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