Structural basis for DNA bending by the architectural transcription factor LEF-1

LYMPHOID enhancer-binding factor (LEF-1) and the closely related T-cell factor 1 (TCF-1) are sequence-specific and cell-type-specific DNA-binding proteins that play important regulatory roles in organogenesis and thymocyte differentiation1–5. LEF-1 participates in regulation of the enhancer associated with the T cell receptor (TCR)-α gene by inducing a sharp bend in the DNA and facilitating interactions between Ets-1, PEBP2-α, and ATF/ CREB transcription factors bound at sites flanking the LEF-1 site1,2,6,7. It seems that LEF-1 plays an architectural role in the assembly and function of this regulatory nucleoprotein complex7,8. LEF-1 recognizes a specific nucleotide sequence through a high-mobility-group (HMG) domain1,2. Proteins containing HMG domains bind DNA in the minor groove, bend the double helix6,9,10, and recognize four-way junctions and other irregular DNA structures9,11. Here we report the solution structure of a complex of the LEF-1 HMG domain and adjacent basic region with its cognate DNA. The structure reveals the HMG domain bound in the widened minor groove of a markedly distorted and bent double helix. The basic region binds across the narrowed major groove and contributes to DNA recognition.

[1]  I Fariñas,et al.  Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. , 1994, Genes & development.

[2]  Stephen K. Burley,et al.  Co-crystal structure of TBP recognizing the minor groove of a TATA element , 1993, Nature.

[3]  K Wüthrich,et al.  Improved efficiency of protein structure calculations from NMR data using the program DIANA with redundant dihedral angle constraints , 1991, Journal of biomolecular NMR.

[4]  Ad Bax,et al.  Three-dimensional heteronuclear NMR of nitrogen-15 labeled proteins , 1989 .

[5]  R Grosschedl,et al.  HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. , 1994, Trends in genetics : TIG.

[6]  Rudolf Grosschedl,et al.  The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures , 1992, Cell.

[7]  A. Gronenborn,et al.  Molecular basis of human 46X,Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex , 1995, Cell.

[8]  Hans Clevers,et al.  An HMG-box-containing T-cell factor required for thymocyte differentiation , 1995, Nature.

[9]  P. Cary,et al.  Solution structure of a DNA-binding domain from HMG1. , 1993, Nucleic acids research.

[10]  P. Goodfellow,et al.  Definition of a consensus DNA binding site for SRY. , 1994, Nucleic acids research.

[11]  P. Donahoe,et al.  An SRY mutation causing human sex reversal resolves a general mechanism of structure-specific DNA recognition: application to the four-way DNA junction. , 1995, Biochemistry.

[12]  R Grosschedl,et al.  Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. , 1995, Genes & development.

[13]  P. Cary,et al.  The DNA sequence specificity of HMG boxes lies in the minor wing of the structure. , 1994, The EMBO journal.

[14]  R Lavery,et al.  The definition of generalized helicoidal parameters and of axis curvature for irregular nucleic acids. , 1988, Journal of biomolecular structure & dynamics.

[15]  J. Keeler,et al.  The solution structure and dynamics of the DNA-binding domain of HMG-D from Drosophila melanogaster. , 1994, Structure.

[16]  K Wüthrich,et al.  Efficient computation of three-dimensional protein structures in solution from nuclear magnetic resonance data using the program DIANA and the supporting programs CALIBA, HABAS and GLOMSA. , 1991, Journal of molecular biology.

[17]  S. Lippard,et al.  Specific binding of chromosomal protein HMG1 to DNA damaged by the anticancer drug cisplatin. , 1992, Science.

[18]  P. Kollman,et al.  An all atom force field for simulations of proteins and nucleic acids , 1986, Journal of computational chemistry.

[19]  P N Goodfellow,et al.  SRY, like HMG1, recognizes sharp angles in DNA. , 1992, The EMBO journal.

[20]  K. Jones,et al.  The hLEF/TCF-1 alpha HMG protein contains a context-dependent transcriptional activation domain that induces the TCR alpha enhancer in T cells. , 1993, Genes & development.

[21]  R Grosschedl,et al.  DNA-binding properties of the HMG domain of the lymphoid-specific transcriptional regulator LEF-1. , 1991, Genes & development.

[22]  H. Clevers,et al.  Sequence‐specific interaction of the HMG box proteins TCF‐1 and SRY occurs within the minor groove of a Watson‐Crick double helix. , 1992, The EMBO journal.

[23]  P. Kraulis,et al.  Structure of the HMG box motif in the B‐domain of HMG1. , 1993, EMBO Journal.

[24]  Steven Hahn,et al.  Crystal structure of a yeast TBP/TATA-box complex , 1993, Nature.

[25]  K. Wüthrich,et al.  Heteronuclear filters in two-dimensional [1H, 1H]-NMR spectroscopy: combined use with isotope labelling for studies of macromolecular conformation and intermolecular interactions , 1990, Quarterly Reviews of Biophysics.

[26]  R Grosschedl,et al.  LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. , 1991, Genes & development.

[27]  K. Jones,et al.  A thymus-specific member of the HMG protein family regulates the human T cell receptor C alpha enhancer. , 1991, Genes & development.

[28]  R. C. Johnson,et al.  The nonspecific DNA-binding and -bending proteins HMG1 and HMG2 promote the assembly of complex nucleoprotein structures. , 1993, Genes & development.

[29]  M. Schumacher,et al.  Crystal structure of LacI member, PurR, bound to DNA: minor groove binding by alpha helices. , 1994, Science.

[30]  H Clevers,et al.  Cloning of murine TCF-1, a T cell-specific transcription factor interacting with functional motifs in the CD3-epsilon and T cell receptor alpha enhancers , 1991, The Journal of experimental medicine.