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The methyl binding domain containing protein MBD5 is a transcriptional regulator responsible for 2q23.1 deletion syndrome.

ABSTRACT: 2Iq23.1 microdeletion syndrome is a recently described rare disease that includes intellectual disability, motor delay, autistic-like behaviors, and craniofacial abnormalities. Dosage insufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene was suggested as the genetic cause, since all the described patients carry a partial or total heterozygous deletion of MBD5. We reported the generation and characterization of a mouse model with haploinsufficiency for Mbd5 that confirmed this hypothesis. As in human 2q23.1 microdeletion syndrome, the MBD5 (+/GT) mouse model exhibited abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities, supporting a causal role for MBD5 in 2q23.1 microdeletion syndrome. The use of mouse neuronal cultures uncovered a deficiency in neurite outgrowth, suggesting the participation of MBD5 in neuronal processes. The study of the MBD5 (+/GT) mouse advanced our understanding of the abnormal brain development associated with behavioral and cognitive symptoms.

SUBMITTER: Walz K

PROVIDER: S-EPMC4755234 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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An epigenetic regulator: methyl-CpG-binding domain protein 1 (MBD1).

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The GAF-like-domain-containing transcriptional regulator DfdR is a sensor protein for dibenzofuran and several hydrophobic aromatic compounds.

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Protein-protein interactions between jasmonate-related master regulator MYC and transcriptional mediator MED25 depend on a short binding domain.

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Project description:Ypd1p, a histidine-containing phosphotransfer protein, plays an important role in a branched His-Asp phosphorelay signal transduction pathway that regulates cellular responses to hyperosmotic stress in Saccharomyces cerevisiae. Ypd1p is required for phosphoryl group transfer from the membrane-bound Sln1p sensor histidine kinase to two downstream response regulator proteins, Ssk1p and Skn7p. To investigate the molecular basis for interaction of Ypd1p with these response regulator domains, we used an approach that coupled alanine-scanning mutagenesis of surface-exposed residues in Ypd1p with a yeast two-hybrid interaction screen. Mutated residues that adversely affected the interaction of Ypd1p with the C-terminal response regulator domain of Ssk1p were identified and found to cluster on or near the alphaA helix in Ypd1p. Our results, supported by analysis of a modeled complex, identify a binding site on Ypd1p for response regulators that is composed of a cluster of conserved hydrophobic residues surrounded by less conserved polar residues. We propose that molecular interactions involving Ypd1p are mediated primarily through hydrophobic contacts, whereas binding specificity and strength of interaction may be influenced by select polar side chain interactions.

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Project description:The methyl-CpG binding domain (MBD) protein MBD4 participates in DNA repair as a glycosylase that excises mismatched thymine bases in CpG sites and also functions in transcriptional repression. Unlike other MBD proteins, MBD4 recognizes not only methylated CpG dinucleotides ((5m)CG/(5m)CG) but also T/G mismatched sites generated by spontaneous deamination of 5-methylcytosine ((5m)CG/TG). The glycosylase activity of MBD4 is also implicated in active DNA demethylation initiated by the deaminase-catalyzed conversion of 5-methylcytosine to thymine. Here, we report the crystal structures of the MBD of MBD4 (MBDMBD4) complexed with (5m)CG/(5m)CG and (5m)CG/TG. The crystal structures show that the DNA interface of MBD4 has flexible structural features and harbors an extensive water network that supports its dual base specificities. Combined with the results of biochemical analyses, the crystal structure of MBD4 bound to 5-hydroxymethylcytosine further demonstrates that MBDMBD4 is able to recognize a wide range of 5-methylcytosine modifications through the unique water network. The versatile base recognition ability of MBDMBD4 implies multifunctional roles for MBD4 in the regulation of dynamic DNA methylation patterns coupled with deamination and/or oxidation of 5-methylcytosine.

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Project description:Estrogen receptor (ER) alpha is an essential component in human physiology and is a key factor involved in the development of breast and endometrial cancers. ERalpha protein levels and transcriptional activity are tightly controlled by the ubiquitin proteasome system. Deubiquitinating enzymes, a class of proteases capable of removing ubiquitin from proteins, are increasingly being seen as key modulators of the ubiquitin proteasome system, regulating protein stability and other functions by countering the actions of ubiquitin ligases. Using mass spectrometry analysis of an ERalpha protein complex, we identified OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) as a novel ERalpha-interacting protein capable of deubiquitinating ERalpha in cells and in vitro. We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells. We also show that OTUB1 regulates the availability and functional activity of ERalpha in Ishikawa cells by affecting the transcription of the ERalpha gene and by stabilizing the ERalpha protein in the chromatin.

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The role of methyl-CpG-binding domain protein-2 (MBD2) in colonic inflammation

Project description:This SuperSeries is composed of the SubSeries listed below.

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Structural basis for ovarian tumor domain-containing protein 1 (OTU1) binding to p97/valosin-containing protein (VCP).

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