Structural basis for the dimerization mechanism of human transcription factor E3

Guang Yang; Peifeng Li; Zaizhou Liu; Siqi Wu; Chen Zhuang; Hang Qiao; Li Zheng; Pengfei Fang; Chuanhu Lei; Jing Wang

doi:10.1016/j.bbrc.2021.06.091

Structural basis for the dimerization mechanism of human transcription factor E3

Biochem Biophys Res Commun. 2021 Sep 10:569:41-46. doi: 10.1016/j.bbrc.2021.06.091. Epub 2021 Jul 2.

Authors

Guang Yang¹, Peifeng Li², Zaizhou Liu², Siqi Wu², Chen Zhuang², Hang Qiao², Li Zheng³, Pengfei Fang³, Chuanhu Lei⁴, Jing Wang⁵

Affiliations

¹ Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences, Shanghai University, 99 Shang-Da Road, Shanghai, 200444, China; State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
² State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
³ State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China; School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China.
⁴ Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences, Shanghai University, 99 Shang-Da Road, Shanghai, 200444, China.
⁵ State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China; School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China. Electronic address: jwang@sioc.ac.cn.

PMID: 34225079
DOI: 10.1016/j.bbrc.2021.06.091

Abstract

The transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) is a member of the microphthalmia (MiT/TFE) transcription factor family. Dysregulation of TFE3 due to chromosomal abnormalities is associated with a subset of human renal cell carcinoma. Little structural information of this key transcription factor has been reported. In this study, we determined the crystal structure of the helix-loop-helix leucine zipper (HLH-Lz) domain of human TFE3 to a resolution of 2.6 Å. The HLH-Lz domain is critical for the dimerization and function of TFE3. Our structure showed that the conserved HLH region formed a four-helix bundle structure with a predominantly hydrophobic core, and the leucine zipper region contributed to the function of TFE3 by promoting dimer interaction and providing partner selectivity. Together, our results elucidated the dimerization mechanism of this important transcription factor, providing the structural basis for the development of inhibiting strategies for treating TFE3 dysregulated diseases.

Keywords: Crystal structure; Dimerization; Helix-loop-helix leucine zipper (HLH-Lz) domain; Microphthalmia (MiT/TFE) transcription factor family; Transcription factor E3 (TFE3).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / metabolism
Crystallography, X-Ray
Gene Expression Regulation
HeLa Cells
Helix-Loop-Helix Motifs*
Humans
Kidney Neoplasms / genetics
Kidney Neoplasms / metabolism
Leucine Zippers*
Models, Molecular
Protein Conformation*
Protein Multimerization*

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
TFE3 protein, human