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A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.

ABSTRACT: TEA domain (TEAD) transcription factors are essential for the normal development of eukaryotes and are the downstream effectors of the Hippo tumor suppressor pathway. Whereas our earlier work established the three-dimensional structure of the highly conserved DNA-binding domain using solution NMR spectroscopy, the structural basis for regulating the DNA-binding activity remains unknown. Here, we present the X-ray crystallographic structure and activity of a TEAD mutant containing a truncated L1 loop, ?L1 TEAD DBD. Unexpectedly, the three-dimensional structure of the ?L1 TEAD DBD reveals a helix-swapped homodimer wherein helix 1 is swapped between monomers. Furthermore, each three-helix bundle in the domain-swapped dimer is a structural homolog of MYB-like domains. Our investigations of the DNA-binding activity reveal that although the formation of the three-helix bundle by the ?L1 TEAD DBD is sufficient for binding to an isolated M-CAT-like DNA element, multimeric forms are deficient for cooperative binding to tandemly duplicated elements, indicating that the L1 loop contributes to the DNA-binding activity of TEAD. These results suggest that switching between monomeric and domain-swapped forms may regulate DNA selectivity of TEAD proteins.

SUBMITTER: Lee DS

PROVIDER: S-EPMC4893915 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.

Lee Dong-Sun DS Vonrhein Clemens C Albarado Diana D Raman C S CS Veeraraghavan Sudha S

Journal of molecular biology 20160322 12

TEA domain (TEAD) transcription factors are essential for the normal development of eukaryotes and are the downstream effectors of the Hippo tumor suppressor pathway. Whereas our earlier work established the three-dimensional structure of the highly conserved DNA-binding domain using solution NMR spectroscopy, the structural basis for regulating the DNA-binding activity remains unknown. Here, we present the X-ray crystallographic structure and activity of a TEAD mutant containing a truncated L1 ...[more]

PMID: 27016204

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Project description:In order to reveal the complex mechanism governing the mitotic/meiotic switch in female germ cells at epigenomic and genomic levels, we examined the chromatin accessibility (scATAC-seq) and the transcriptional dynamics (scRNA-seq) in germ cells of mouse embryonic ovary between E11.5 to 13.5 at single-cell resolution. Adopting a strict transcription factors (TFs) screening framework that makes it easier to understand the single-cell chromatin signature and a TF interaction algorithm that integrates the transcript levels, chromatin accessibility, and motif scores, we identified 14 TFs potentially regulating the mitotic/meiotic switch, including TCFL5, E2F1, E2F2, E2F6, E2F8, BATF3, SP1, FOS, FOXN3, VEZF1, GBX2, CEBPG, JUND, and TFDP1. Focusing on TCFL5, we constructed Tcfl5+/- mice which showed significantly reduced fertility and found that decreasing TCFL5 expression in cultured E12.5 ovaries by RNAi impaired meiotic progression from leptotene to zygotene. Bioinformatics analysis of published results of the embryonic germ cell transcriptome and the finding that in these cells central meiotic genes (Stra8, Tcfl5, Sycp3, and E2f2) possess open chromatin status already at the mitotic stage together with other features of TCFL5 (potential capability to interact with core TFs and activate meiotic genes, its progressive activation after preleptotene, binding sites in the promoter region of E2f2 and Sycp3), indicated extensive amplification of transcriptional programs associated to mitotic/meiotic switch with an important contribution of TCFL5. We conclude that the identified TFs, are involved in various stages of the mitotic/meiotic switch in female germ cells, TCFL5 primarily in meiotic progression. Further investigation on these factors might give a significant contribution to unravel the molecular mechanisms of this fundamental process of oogenesis and provide clues about pathologies in women such as primary ovarian insufficiency (POI) due at least in part to meiotic defects.

Dataset Information

A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.

Publications

A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.

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