Crystal Structure of the MATa1/MATα2 Homeodomain Heterodimer Bound to DNA

Li, Thomas; Stark, Martha R.; Johnson, Alexander D.; Wolberger, Cynthia

doi:10.1126/science.270.5234.262

Cited by 263 publications

(286 citation statements)

References 61 publications

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“…Helices al and a3 form the HTH motif of the homeodomain, with helix a3 (also known as the recognition helix) interacting with base pairs in the major groove of the DNA. The Pit-1 homeodomain resembles other homeodomain-DNA crystal structures (Kissinger et al 1990;Wolberger et al 1991;Hirsch and Aggarwal 1995;Li et al 1995;Wilson et al 1995), except for a striking deviation at the carboxy-terminal end of the recognition helix. The last four residues of the recognition helix are in an unraveled or extended conformation that is closer to the NMR structures of some homeodomains.…”

Section: Homeodomains and Dna Contactsmentioning

confidence: 73%

“…Each interface loses -600 A^ of solvent accessible surface area. The dimerization contacts can be compared with those observed in the DNA complexes of Drosophila Paired homeodomain homodimer and the yeast Mata2/Matal homeodomain heterodimer (Li et al 1995;Wilson et al 1995). In the Paired complex, the amino-terminal arm and the amino terminus of helix a3 of one homeodomain contact the first few residues of helices a2 and a3 of the twofold related homeodomain.…”

Section: Dimer Interfacementioning

confidence: 99%

“…Analogous to the Pit-1 complex, the interacting surfaces are complementary in terms of both polar and nonpolar interactions. In contrast, the interface in the Mata2/Matal heterodimer is predominately hydrophobic,-resulting in a total buried surface area of 754A^ (Li et al 1995). Mata2 contains a carboxy-terminal tail, immediately following the homeodomain, that becomes ordered in the presence of Matal to assume a helical conformation.…”

Section: Dimer Interfacementioning

confidence: 99%

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Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Jacobson¹,

Leon-Del-Rio²,

Rosenfeld³

et al. 1997

Genes Dev.

191

143

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Pit-1, a member of the POU domain family of transcription factors, characterized by a bipartite DNA-binding domain, serves critical developmental functions based on binding to diverse DNA elements in its target genes. Here we report a high resolution X-ray analysis of the Pit-1 POU domain bound to a DNA element as a homodimer. This analysis reveals that Pit-1 subdomains bind to perpendicular faces of the DNA, rather than opposite faces of the DNA as in Oct-1. This is accomplished by different spacing and orientation of the POU-specific domain. Contrary to previous predictions, the dimerization interface involves the carboxyl terminus of the DNA recognition helix of the homeodomain, which in an extended conformation interacts with specific residues at the amino terminus of helix al and in the loop between helices a3 and a4 of the POU-specific domain of the symmetry related monomer. These features suggest the molecular basis of disease-causing mutations in Pit-1 and provide potential basis for the flexible allostery between protein domains and DNA sites in the activation of target genes.[Key Words: Crystal structure; Pit-1; POU-domain factors; dimerization; spacing; orientation] Received October 25, 1996; revised version accepted December 3, 1996.The expression of specific genes in cells is often governed by families of transcription factors harboring DNA-binding motifs. In eukaryotes, these factors often exhibit extraordinary versatility. For instance, the bZip and helix-loop-helix families of transcription factors bind to DNA as both homo-and heterodimers (Bexevanis and Vinson 1993;Glover and Harrison 1995). The nuclear receptors go a step further and recognize DNA elements with different spacings and polarities between the half-sites (Naar et al. 1991;Umesono et al. 1991;Kurokawa et al. 1993). The POU domain family of transcription factors are perhaps the most remarkable in their ability to bind DNA as both monomers and dimers and in their ability to adopt diverse configurations (Wegner et al. 1993;Herr and Cleary 1995). Part of this versatility derives from their unusual bipartite structure, consisting of a highly conserved -75 amino acid POUspecific domain (POUg), tethered by a linker of variable length and composition, to a 60-amino-acid homeodomain (POUH). The flexibility of the linker, in particular, allows the possibility of different relative spacings and orientations between the subdomains. This helps to exThese authors contributed equally to this work. "Corresponding author. Present address:

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Section: Homeodomains and Dna Contactsmentioning

confidence: 73%

Section: Dimer Interfacementioning

confidence: 99%

Section: Dimer Interfacementioning

confidence: 99%

See 1 more Smart Citation

Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Jacobson¹,

Leon-Del-Rio²,

Rosenfeld³

et al. 1997

Genes Dev.

191

143

View full text Add to dashboard Cite

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“…Thus, the binding properties of the ZF-HD family members may differ from other HDs with a Phe at position 49. Various HD-DNA structures have been crystallized (Kissinger et al, 1990;Wolberger et al, 1991;Klemm et al, 1994;Hirsch and Aggarwal, 1995;Li et al, 1995;Wilson et al, 1995;Passner et al, 1999;Piper et al, 1999) and the critical residues for contacting DNA have been identified. Based on these studies, the N-terminal arm of the HD forms contacts with the DNA minor groove.…”

Section: The Zf-hd Proteins Possess a Variant Hdmentioning

confidence: 99%

The Arabidopsis Zinc Finger-Homeodomain Genes Encode Proteins with Unique Biochemical Properties That Are Coordinately Expressed during Floral Development

2006

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Arabidopsis (Arabidopsis thaliana) contains approximately 100 homeobox genes, many of which have been shown to play critical roles in various developmental processes. Here we characterize the zinc finger-homeodomain (ZF-HD) subfamily of homeobox genes, consisting of 14 members in Arabidopsis. We demonstrate that the HDs of the ZF-HD proteins share some similarities with other known HDs in Arabidopsis, but they contain distinct features that cluster them as a unique class of plant HD-containing proteins. We have carried out mutational analyses to show that the noncanonical residues present in the HDs of this family of proteins are important for function. Yeast (Saccharomyces cerevisiae) two-hybrid matrix analyses of the ZF-HD proteins reveal that these proteins both homo-and heterodimerize, which may contribute to greater selectivity in DNA binding. These assays also show that most of these proteins do not contain an intrinsic activation domain, suggesting that interactions with other factors are required for transcriptional activation. We also show that the family members are all expressed predominantly or exclusively in floral tissue, indicating a likely regulatory role during floral development. Furthermore, we have identified loss-of-function mutations for six of these genes that individually show no obvious phenotype, supporting the idea that the encoded proteins have common roles in floral development. Based on these results, we propose the ZF-HD gene family encodes a group of transcriptional regulators with unique biochemical activities that play overlapping regulatory roles in Arabidopsis floral development.

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“…Several structures of homeodomain-DNA complexes have been published by Wolberger and coworkers, including homeodomain mating type protein complexes in yeast [38][39][40][41]35] corresponding to PDB identifiers 1APL, 1YRN, 1AKH, 1LE8, and 1K61.…”

Section: Resultsmentioning

confidence: 99%

Decoding transcriptional regulatory interactions

Liu

Bader

2006

Physica D: Nonlinear Phenomena

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Transcription factor proteins control the temporal and spatial expression of genes by binding specific regulatory elements, or motifs, in DNA. Mapping a transcription factor to its motif is an important step towards defining the structure of transcriptional regulatory networks and understanding their dynamics. The information to map a transcription factor to its DNA binding specificity is in principle contained in the protein sequence. Nevertheless, methods that map directly from protein sequence to target DNA sequence have been lacking, and generation of regulatory maps has required experimental data. Here we describe a purely computational method for predicting transcription factor binding. The method calculates the free energy of binding between a transcription factor and possible target DNA sequences using thermodynamic integration. Approximations of additivity (each DNA basepair contributes independently to the binding energy) and linear response (the DNAprotein and DNA-solvent couplings are linear in an effective reaction coordinate representing the basepair character at a specific position) make the computations feasible and can be verified by more detailed simulations. Results obtained for MAT-α2, a yeast homeodomain transcription factor, are in good agreement with known results. This method promises to provide a general, computationally feasible route from a genome sequence to a gene regulatory network.

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Crystal Structure of the MATa1/MATα2 Homeodomain Heterodimer Bound to DNA

Cited by 263 publications

References 61 publications

Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility.

The Arabidopsis Zinc Finger-Homeodomain Genes Encode Proteins with Unique Biochemical Properties That Are Coordinately Expressed during Floral Development

Decoding transcriptional regulatory interactions

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