Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.

Giese, K; Kingsley, C; Kirshner, J R; Grosschedl, R

doi:10.1101/gad.9.8.995

PreprintCited by 541Genomics and Chromatin DynamicsT-cell and B-cell ImmunologyDevelopmental Biology and Gene Regulation

Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.

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Giese, K, Kingsley, C, Kirshner, J R, Grosschedl, R·1995·Genes & Development

DOI 10.1101/gad.9.8.995

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Abstract

In this study we examine the molecular basis for the synergistic regulation of the minimal TCR alpha enhancer by multiple proteins. We find that reconstitution of TCR alpha enhancer function in nonlymphoid cells requires expression of the lymphoid-specific proteins LEF-1, Ets-1 and PEBP2 alpha (CBF alpha), and a specific arrangement of their binding sites in the enhancer. We show that Ets-1 cooperates with PEBP2 alpha to bind adjacent sites at one end of the enhancer, forming a ternary complex that is unstable by itself. Stable occupancy of the Ets-1- and PEBP2 alpha-binding sites in a DNase I protection assay was found to depend on both a specific helical phasing relationship with a nonadjacent ATF/CREB-binding site at the other end of the enhancer and on LEF-1. The HMG domain of LEF-1 was found previously to bend the DNA helix in the center of the TCR alpha enhancer. We now show that the HMG domain of the distantly related SRY protein, which also bends DNA, can partially replace LEF-1 in stimulating enhancer function in transfection assays. Taken together with the observation that Ets-1 and members of the ATF/CREB family have the potential to associate in vitro, these data suggest that LEF-1 can coordinate the assembly of a specific higher-order enhancer complex by facilitating interactions between proteins bound at nonadjacent sites.

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AML1 interacts with Ets-1, and in this case the runt domain contacts amino acids 123 to 240 in the Ets-1 N terminus rather than the conserved ets DNA-binding domain.
“Although AML1 is known to interact with Ets-1, which like PU.1 is a member of the ets family of transcription factors, in this situation it is not the conserved ets DNA-binding domain which makes contact with the runt domain of AML1, but rather amino acids 123 to 240 in the N terminus of Ets-1 (18).”
From Multiple Functional Domains of AML1: PU.1 and C/EBPα Synergize with Different Regions of AML1 (1998) · cites this paper as [18]
Prior studies report that physical interaction between transcription factors can enhance DNA binding, which may explain synergy when two factors are present.
“In several studies, the physical interaction between transcription factors increases DNA-binding ability, providing an explanation for synergistic activation in the presence of two factors (11,18,56,58,67).”
From Multiple Functional Domains of AML1: PU.1 and C/EBPα Synergize with Different Regions of AML1 (1998) · cites this paper as [18]
Ets-1 stimulates DNA binding by CBFα2.
“Both the CBF b subunit and the DNA-binding protein Ets-1 stimulate DNA binding by the CBF a 2 protein.”
From Auto-Inhibition and Partner Proteins, Core-Binding Factor β (CBFβ) and Ets-1, Modulate DNA Binding by CBFα2 (AML1) (2000) · cites this paper as [19]

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Authors: Giese, K., Kingsley, C., Kirshner, J. R., & Grosschedl, R.
Affiliations: Howard Hughes Medical Institute (US)
ORCID: Kirshner, J R
Grosschedl, R
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1995-04-15
Volume: 9
Issue: 8
Pages: 995-1008
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.9.8.995
OpenAlex: W2130002948
Cited by: 541
References: 74
Citations by year: 2026: 2 · 2025: 7 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 6 · 2016: 4 · 2015: 5 · 2014: 10 · 2013: 9 · 2012: 17
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
McKnight Foundation
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords: LEF1, ETS1, DNA bending, HMG domain, protein-protein interaction, transcriptional regulation
MeSH terms: Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Blood Proteins, Cells, Cultured, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Models, Genetic, Molecular Sequence Data, Nucleic Acid Conformation, Protein Binding, Proto-Oncogene Proteins, Transcription Factors, Transcription, Genetic, Receptors, Antigen, T-Cell, alpha-beta, Cyclic AMP Response Element-Binding Protein, Macromolecular Substances, Transcription Factor AP-2, Core Binding Factor alpha Subunits, Proto-Oncogene Proteins c-ets, Proto-Oncogene Protein c-ets-1, Activating Transcription Factors, Lymphoid Enhancer-Binding Factor 1

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Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.

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