人类转录因子 E3 二聚化机制的结构基础。

Structural basis for the dimerization mechanism of human transcription factor E3.

机构信息

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.

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.

出版信息

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

DOI:10.1016/j.bbrc.2021.06.091

PMID:34225079

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.

摘要

免疫球蛋白重链增强子 3（TFE3）的转录因子是小眼畸形（MiT/TFE）转录因子家族的成员。染色体异常导致的 TFE3 失调与人类肾细胞癌的一个亚群有关。这个关键转录因子的结构信息很少有报道。在这项研究中，我们确定了人 TFE3 的螺旋-环-螺旋亮氨酸拉链（HLH-Lz）结构域的晶体结构，分辨率为 2.6 Å。HLH-Lz 结构域对于 TFE3 的二聚化和功能至关重要。我们的结构表明，保守的 HLH 区域形成了一个四螺旋束结构，具有主要的疏水性核心，亮氨酸拉链区域通过促进二聚体相互作用和提供伙伴选择性来促进 TFE3 的功能。总之，我们的结果阐明了这个重要转录因子的二聚化机制，为开发治疗 TFE3 失调疾病的抑制策略提供了结构基础。