Crystal structure of MEF2A core bound to DNA at 1.5 Å resolution

Santelli, Eugenio; Richmond, Timothy J.

doi:10.1006/jmbi.2000.3568

Cited by 110 publications

(154 citation statements)

References 55 publications

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“…Using electrophoretic mobility shift assays, we demonstrated that HDAC7 was able to bind to the DNA-MEF2C complex, suggesting that different interaction surfaces are responsible for DNA binding and dimerization, and HDACs association. Indeed, mutational and structural studies demonstrate that the region that contacts DNA differs from the region responsible for HDAC4 binding (42,58). We conclude that HDAC7 represses transcription activity of MEF2 through its associated repressor activity.…”

Section: Hdac7 Modulates Mef2 Activity Through Direct Physicalmentioning

confidence: 79%

Mechanism for Nucleocytoplasmic Shuttling of Histone Deacetylase 7

Kao¹,

Verdel²,

Tsai³

et al. 2001

Journal of Biological Chemistry

212

224

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Here we show that HDAC7, a member of the class II histone deacetylases, specifically targets several members of myocyte enhancer factors, MEF2A, -2C, and -2D, and inhibits their transcriptional activity. Furthermore, we demonstrate that DNA-bound MEF2C is capable of recruiting HDAC7, demonstrating that the HDAC7-dependent repression of transcription is not due to the inhibition of the MEF2 DNA binding activity. The data also suggest that the promoter bound MEF2 is potentially capable of remodeling adjacent nucleosomes via the recruitment of HDAC7. We have also observed a nucleocytoplasmic shuttling of HDAC7 and dissected the mechanism involved. In NIH3T3 cells, HDAC7 was primarily localized in the cytoplasm, essentially due to an active CRM1-dependent export of the protein from the nucleus. Interestingly, in HeLa cells, HDAC7 was predominantly nuclear. In these cells we could restore the cytoplasmic localization of HDAC7 by expressing CaMK I. This CaMK I-induced nuclear export of HDAC7 was abolished when three critical serines, Ser-178, Ser-344, and Ser-479, of HDAC7 were mutated. We show that these serines are involved in the direct interaction of HDAC7 with 14-3-3. Mutations of these serine residues weakened the association with 14-3-3 and dramatically enhanced the repression activity of HDAC7 in NIH3T3 cells, but not in HeLa cells. Data presented in this work clearly show that the signal dependent subcellular localization of HDAC7 is essential in controlling its activities. The data also show that the cellular concentration of factors such as 14-3-3, CaMK I, and other yet unknown molecules may determine the subcellular localization of an individual HDAC member in a cell type and HDACspecific manner.Regulation of gene expression in eukaryotic cells is achieved through the recruitment of promoter-specific transcription factors and the basal transcription apparatus associated with the reorganization of chromatin on the promoter. Recent studies strongly suggest that the amino-terminal tail of histones play a critical role in the chromatin structure and hence, the regulation of gene expression (1-5). The amino-terminal tails of histones are targets for several modifications including methylation, phosphorylation, and acetylation. While histone acetylation at specific lysines is associated with transcriptional activation, deacetylated histones are found in transcriptionally silent regions. The acetylation status of the histone tails is determined by the interplay between histone acetyltransferases and histone deacetylases (HDACs).1 It has been recently suggested that promoter-specific transcription factors recruit either coactivators or co-repressors to achieve their positive or negative regulation. Notably, co-activators such as CBP/p300, PCAF, and p160 family proteins possess intrinsic histone acetyltransferase activity and therefore, normally activate transcription (6 -10). By contrast, co-repressors such as SMRT, N-CoR, and mSin3A recruit HDACs to repress transcription (11-15). In several cases, physical associ...

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Section: Hdac7 Modulates Mef2 Activity Through Direct Physicalmentioning

confidence: 79%

Mechanism for Nucleocytoplasmic Shuttling of Histone Deacetylase 7

Kao¹,

Verdel²,

Tsai³

et al. 2001

Journal of Biological Chemistry

212

224

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“…The N-terminal DNA-contacting half of the MADS domain forms an amphipathic a-helix that contacts DNA and contributes to the strength of dimerization. The C-terminal half of MADS domain forms a series of anti-parallel b-sheets that function as a dimerization interface (Hassler and Richmond, 2001;Pellegrini et al, 1995;Santelli and Richmond, 2000;Tan and Richmond, 1998). We did not address critical amino acids in the MADS domain in the reverse yeast two-hybrid screens due to the fact that MADS domain-containing versions of AP3 and PI do not interact strongly in yeast two-hybrid assays.…”

Section: Discussionmentioning

confidence: 99%

“…The 56-amino acid MADS domain possesses both DNA-binding and dimerization functions as demonstrated by X-ray structures of the MADS domains of the mammalian proteins SRF and MEF2 and the yeast protein MCM1. The amino terminal end of the MADS domain contacts DNA while the C-terminal end contains two anti-parallel b sheets that function as a dimerization interface (Figure 1) (Hassler and Richmond, 2001;Pellegrini et al, 1995;Santelli and Richmond, 2000;Tan and Richmond, 1998). The 80-amino acid K domain contains several (abcdefg) n heptad repeats in which a and d positions are occupied by hydrophobic amino acids suggesting that K domain forms a series of amphipathic a-helices (Ma et al, 1991;Riechmann and Meyerowitz, 1997b).…”

Section: Introductionmentioning

confidence: 99%

The K domain mediates heterodimerization of theArabidopsisfloral organ identity proteins, APETALA3 and PISTILLATA

2003

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SummaryMADS genes in plants encode key developmental regulators of vegetative and reproductive development. The majority of well-characterized plant MADS proteins contain two conserved domains, the DNA-binding MADS domain and the K domain. The K domain is predicted to form three amphipathic a-helices referred to as K1, K2, and K3. In this report, we define amino acids and subdomains important for heterodimerization between the two Arabidopsis floral organ identity MADS proteins APETALA3 (AP3) and PISTILLATA (PI). Analysis of mutants defective in dimerization demonstrates that K1, K2 and the region between K1 and K2 are critical for the strength of AP3/PI dimerization. The majority of the critical amino acids are hydrophobic indicating that the K domain mediates AP3/PI interaction primarily through hydrophobic interactions. Specially, K1 of AP3 and PI resembles a leucine zipper motif. Most mutants defective in AP3/PI heterodimerization in yeast exhibit partial floral organ identity function in transgenic Arabidopsis. Our results also indicate that the motif containing Asn-98 and specific charged residues in K1 (Glu-97 in PI and Arg-102 in AP3) are important for both the strength and specificity of AP3/PI heterodimer formation.

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“…3). Two of the residues were found within the MADS and correspond to amino acids that in other MADSdomain proteins participate in interactions between subunits (44)(45)(46). For example, site 42 is homologous to a site that in the myocyte enhancer factor-2 has been shown to intervene in subunit folding (45).…”

Section: Mads-box Gene Family Phylogenymentioning

confidence: 99%

Adaptive evolution in the Arabidopsis MADS-box gene family inferred from its complete resolved phylogeny

Martínez-Castilla

Álvarez-Buylla²

2003

Proc. Natl. Acad. Sci. U.S.A.

131

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Gene duplication is a substrate of evolution. However, the relative importance of positive selection versus relaxation of constraints in the functional divergence of gene copies is still under debate. Plant MADS-box genes encode transcriptional regulators key in various aspects of development and have undergone extensive duplications to form a large family. We recovered 104 MADS sequences from the Arabidopsis genome. Bayesian phylogenetic trees recover type II lineage as a monophyletic group and resolve a branching sequence of monophyletic groups within this lineage. The type I lineage is comprised of several divergent groups. However, contrasting gene structure and patterns of chromosomal distribution between type I and II sequences suggest that they had different evolutionary histories and support the placement of the root of the gene family between these two groups. Site-specific and sitebranch analyses of positive Darwinian selection (PDS) suggest that different selection regimes could have affected the evolution of these lineages. We found evidence for PDS along the branch leading to flowering time genes that have a direct impact on plant fitness. Sites with high probabilities of having been under PDS were found in the MADS and K domains, suggesting that these played important roles in the acquisition of novel functions during MADS-box diversification. Detected sites are targets for further experimental analyses. We argue that adaptive changes in MADSdomain protein sequences have been important for their functional divergence, suggesting that changes within coding regions of transcriptional regulators have influenced phenotypic evolution of plants.ene duplication provides a substrate for evolution, and understanding the fate of duplicates is fundamental to clarifying mechanisms of genetic redundancy and the link between gene family diversification and phenotypic evolution (1). Several empirical studies have evaluated the roles of duplication in adaptation and diversification (2), but the evolutionary forces at play during functional divergence of duplicates are still under debate (3, 4). Genomic studies are revealing that eukaryotes harbor large families of genes that have arisen during evolution through duplication and have persisted for longer periods of time than expected by classical models (5). Models that incorporate positive selection (6, 7) provide alternative explanations for the persistence of duplicates.Empirical studies to test models on the fate of duplicates and the evolutionary forces driving their functional divergence will need complete and resolved gene family phylogenies. Several studies suggest that positive Darwinian selection (PDS) might have been important in protein evolution. However, most previous studies have involved few members of a gene family from various species (8,9). In this article, we annotate, align, and analyze the complete MADS-box gene family of the plant model system Arabidopsis thaliana and provide resolved phylogenies as a basis to infer the role of PDS in protein ...

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Crystal structure of MEF2A core bound to DNA at 1.5 Å resolution

Cited by 110 publications

References 55 publications

Mechanism for Nucleocytoplasmic Shuttling of Histone Deacetylase 7

Mechanism for Nucleocytoplasmic Shuttling of Histone Deacetylase 7

The K domain mediates heterodimerization of theArabidopsisfloral organ identity proteins, APETALA3 and PISTILLATA

Adaptive evolution in the Arabidopsis MADS-box gene family inferred from its complete resolved phylogeny

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