Structure of the GCM domain-DNA complex: a DNA-binding domain with a novel fold and mode of target site recognition

Cohen, Serge; Moulin, Martine; Hashemolhosseini, Said; Kilian, Karin; Wegner, Michael; Müller, Christoph W.

doi:10.1093/emboj/cdg182

Cited by 74 publications

(83 citation statements)

References 50 publications

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“…Protein Modeling-The model for the GCM motif (residues 14 -167) of human GCMa protein was constructed by a homology-based modeling method using MODELER version 8.2 (Accelrys, San Diego, CA) based on the 2.9 Å resolution crystal structure of the GCM motif of murine GCMa bound to its octameric DNA target (Protein Data Bank code 1ODH) (15). The GCM motifs of human and murine GCMa proteins share 93.5% amino acid sequence identity, and there are no gaps in the sequence alignment.…”

Section: Methodsmentioning

confidence: 99%

Small Ubiquitin-like Modifier Modification Regulates the DNA Binding Activity of Glial Cell Missing Drosophila Homolog a

Chou

Chang

Liu

et al. 2007

Journal of Biological Chemistry

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Glial cell missing Drosophila homolog a (GCMa) is an essential transcription factor for placental development, which controls the differentiation of the syncytiotrophoblast layer. Although the activity of GCMa can be post-translationally regulated by protein phosphorylation, ubiquitination, and acetylation, it is unknown whether GCMa activity can be regulated by sumoylation. In this report, we investigated the role of sumoylation in the regulation of GCMa activity. We demonstrated that Ubc9, the E2 component of the sumoylation machinery, specifically interacts with the N-terminal domain of GCMa and promotes GCMa sumoylation on lysine 156. Moreover, GCMa-mediated transcriptional activation was repressed by sumoylation but was enhanced in the presence of the SUMO-specific protease, SENP1. The repressive effect of sumoylation on GCMa transcriptional activity was attributed to decreased DNA binding activity of GCMa. Furthermore, structural analysis revealed a steric clash between the SUMO1 moiety of sumoylated GCMa and the DNA-binding surfaces of GCMa, which may destabilize the interaction between GCMa and its cognate DNA sequence. Our study demonstrates that GCMa is a new sumoylation substrate and its activity is down-regulated by sumoylation.

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Section: Methodsmentioning

confidence: 99%

Small Ubiquitin-like Modifier Modification Regulates the DNA Binding Activity of Glial Cell Missing Drosophila Homolog a

Chou

Chang

Liu

et al. 2007

Journal of Biological Chemistry

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“…Homology modeling of the DNA-binding domain of wild-type and mutant human GCM2 proteins was based on the X-ray crystal structure of the murine DNA-binding domain of GCM1 protein complexed with octameric DNA (PDB id: 1ODH) (38). Murine and human species have a sequence identity of 69% in the region (residues 19-173).…”

Section: Structure Of Mutant Gcm2 Protein By Construction Of Three-dimentioning

confidence: 99%

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Tomar¹,

Bora²,

Singh³

et al. 2010

European Journal of Endocrinology

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Objective: Glial cells missing 2 (GCM2) gene encodes a parathyroid-specific transcription factor. We assessed GCM2 gene sequence in patients with isolated hypoparathyroidism (IH). Design: Case-control study. Methods: Complete DNA sequencing of the GCM2 gene including its exons, promoter, and 5 0 and 3 0UTRs was performed in 24/101 patients with IH. PCR-restriction fragment length polymorphism was used to detect a novel R110W mutation in all 101 IH patients and 655 healthy controls. Significance of the mutation was assessed by electrophoretic mobility shift assay (EMSA) and nuclear localization on transfection.Results: A heterozygous R110W mutation was present in DNA-binding domain in 11/101 patients (10.9%) and absent in 655 controls (P!10 K7 ). Four of 13 nonaffected first-degree relatives for five of these index cases had R110W mutation. Four heterozygous single nucleotide polymorphisms were found in the 5 0 region. One of the 11 patients with R110W also had T370M change in compound heterozygous form. Mutant R110W and T370M GCM2 proteins showed decreased binding with GCM recognition elements on EMSA indicating loss of function. Both wild-type and R110W mutant GCM2 proteins showed nuclear localization. Conclusions: The present study indicates a significant association of R110W variant with IH. Absence of effect of heterozygous R110W mutation on DNA binding and presence of the same mutation in asymptomatic family members indicate that additional genetic (akin to T370M change) or nongenetic factors might contribute to the expression of diseases in IH. Alternatively, it is possible that association of R110W with IH could be due to linkage disequilibrium with the unidentified relevant genes in IH.

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“…We found two DNA binding domain structures of marginal similarity to WRKY4-C, Arabidopsis NAC (no apical meristem) (PDB code 1ut4; Ernst et al, 2004) (Z-score 2.6) and Drosophila GCM (glia cell missing) (PDB code 1odh; Cohen et al, 2003) (Z-score 2.2), which are transcription factors that have functional similarities to WRKY4-C (Figure 8). Like other partly similar structures, they are significantly larger than WRKY4-C and possess antiparallel b-sheets of four strands or more as substructures.…”

Section: Similarity To Other Structuresmentioning

confidence: 99%

“…The structure of the GCM DNA binding domain was determined in complex with DNA (Cohen et al, 2003) (Figure 8B). This structure possesses a small four-stranded antiparallel b-sheet, which was aligned to the WRKY4-C b-sheet using the DALI program.…”

Section: Similarity To Other Structuresmentioning

confidence: 99%

Solution Structure of an Arabidopsis WRKY DNA Binding Domain

et al. 2005

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The WRKY proteins comprise a major family of transcription factors that are essential in pathogen and salicylic acid responses of higher plants as well as a variety of plant-specific reactions. They share a DNA binding domain, designated as the WRKY domain, which contains an invariant WRKYGQK sequence and a CX 4-5 CX 22-23 HXH zinc binding motif. Herein, we report the NMR solution structure of the C-terminal WRKY domain of the Arabidopsis thaliana WRKY4 protein. The structure consists of a four-stranded b-sheet, with a zinc binding pocket formed by the conserved Cys/His residues located at one end of the b-sheet, revealing a novel zinc and DNA binding structure. The WRKYGQK residues correspond to the most N-terminal b-strand, kinked in the middle of the sequence by the Gly residue, which enables extensive hydrophobic interactions involving the Trp residue and contributes to the structural stability of the b-sheet. Based on a profile of NMR chemical shift perturbations, we propose that the same strand enters the DNA groove and forms contacts with the DNA bases.

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Structure of the GCM domain-DNA complex: a DNA-binding domain with a novel fold and mode of target site recognition

Cited by 74 publications

References 50 publications

Small Ubiquitin-like Modifier Modification Regulates the DNA Binding Activity of Glial Cell Missing Drosophila Homolog a

Small Ubiquitin-like Modifier Modification Regulates the DNA Binding Activity of Glial Cell Missing Drosophila Homolog a

Presence and significance of a R110W mutation in the DNA-binding domain of GCM2 gene in patients with isolated hypoparathyroidism and their family members

Solution Structure of an Arabidopsis WRKY DNA Binding Domain

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