The structure of the Dead ringer-DNA complex reveals how AT-rich interaction domains (ARIDs) recognize DNA

Iwahara, Junji; Iwahara, Mizuho; Daughdrill, Gary W.; Ford, Jennifer B.; Clubb, Robert T.

doi:10.1093/emboj/21.5.1197

Cited by 64 publications

(130 citation statements)

References 82 publications

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“…A mutation at P268 greatly decreased DNA binding activity. This residue is within the ␤-sheet that is speculated to serve as a stabilizing factor in protein-DNA interaction (18). Of the mutants introduced in Bright, Trp 299 is present within helix 5, Phe 317 is within helix 6, and Tyr 330 is found in helix 7.…”

Section: Discussionmentioning

confidence: 99%

“…This human protein appears to be a truncated isoform of the human Bright/Dril1 homologue. E2FBP1 was shown to interact with the cell cycle regulatory protein E2F through interactions that included the REKLES sequence (18). Therefore, this motif may be important for interaction of Bright with additional proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The crystal structure of the ARID region of Dri has been solved and revealed a unit of eight ␣-helices with a short two-stranded anti-parallel ␤-sheet (17). NMR analysis predicted that helices 5 and 6 together with the intervening loop would contact DNA within the major groove (18). Because of the greater than 90% homology of Bright and Dri within the ARID region (19), the crystal structures may be quite similar.…”

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confidence: 99%

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Mutations in the DNA-binding Domain of the Transcription Factor Bright Act as Dominant Negative Proteins and Interfere with Immunoglobulin Transactivation

Nixon

Rajaiya

Webb

2004

Journal of Biological Chemistry

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The transcription factor Bright (or B cell regulator of IgH transcription) is a B cell-specific protein that was first discovered in a mature mouse B cell line, BCg3R1-d, as a mobilityshifted protein complex that caused 3-6-fold increases in heavy chain mRNA levels in response to stimulation with a T-dependent antigen and interleukin-5 (1, 2). Bright binds to AϩT-rich regions of the intronic heavy chain enhancer that have been identified as matrix association regions and regions 5Ј of some V H promoters, including the V1 S107 family gene (3, 4). The cDNA for Bright was isolated in 1995, and the protein was shown to interact with DNA as a multimeric complex that includes multiple copies of Bright (4).Recent studies suggest that Bruton's tyrosine kinase (〉tk), 1 the defective enzyme in xid (X-linked immunodeficiency disease) mice, is a component of the Bright DNA-binding complex (5). xid mice exhibit deficiencies in B cell development and abnormalities in immunoglobulin production (6, 7). Initial evidence indicated that the Bright DNA-binding complex was supershifted by antibodies that reacted with several different domains of Btk (5). Furthermore, Bright co-precipitated with Btk from wild type, activated splenic B cells, but Btk and Bright did not co-precipitate from xid B cells despite both proteins being present. These data suggested that Bright and Btk are functionally linked. However, the role of Bright in normal B cell development is unknown. Expression of Bright in both mouse and human tissues is tightly regulated at the level of transcription (8, 9). In the mouse, Bright mRNA was detected in all embryonic tissues, but became B-lymphocyte restricted in the adult. Bright mRNA is apparent at the pre-B and activated germinal center stages of B cell differentiation (8). The human Bright homologue (10) shows a similar expression pattern in the adult where mRNA expression is primarily limited to B lymphocytes of the pro-B cell, germinal center centroblasts, and mature recirculating subpopulations (9). Thus, in both the adult mouse and human, Bright expression is predominantly B cell-specific.Bright belongs to a growing family of proteins that bind DNA through an AϩT-rich interacting domain (ARID) (11). ARIDcontaining proteins are highly conserved throughout evolution where many of them play important roles as developmental regulators (11). ARID-containing proteins occur in all eukaryotic organisms and include 13 sequences in the human data base (11,12). Bright is the only member of the ARID family for which gene target sequences have been identified. One of the best characterized members of this family is the Dri (Drosophila homologue Dead Ringer) gene, first identified in 1996 (13). The ARID region of Dri is essential for anterior-posterior patterning and for muscle development in the fly embryo (14 -16). The crystal structure of the ARID region of Dri has been solved and revealed a unit of eight ␣-helices with a short two-stranded anti-parallel ␤-sheet (17). NMR analysis predicted that helices 5 and 6 together ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mutations in the DNA-binding Domain of the Transcription Factor Bright Act as Dominant Negative Proteins and Interfere with Immunoglobulin Transactivation

Nixon

Rajaiya

Webb

2004

Journal of Biological Chemistry

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“…1 H, 13 C, and 15 N protein chemical shift assignments were obtained using standard methods (41,42). Chemical shift assignments for the sorting signal were obtained by analyzing two-dimensional (F1,F2) 13 C-filtered NOESY (43) and (F1) 13 C-filtered TOCSY (44) spectra.…”

Section: Preparation Of the Covalent Complex For Nmr Studies-mentioning

confidence: 99%

The Structure of the Staphylococcus aureus Sortase-Substrate Complex Reveals How the Universally Conserved LPXTG Sorting Signal Is Recognized

Suree¹,

Liew²,

Villareal³

et al. 2009

Journal of Biological Chemistry

181

369

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In Gram-positive bacteria, sortase enzymes assemble surface proteins and pili in the cell wall envelope. Sortases catalyze a transpeptidation reaction that joins a highly conserved LPXTG sorting signal within their polypeptide substrate to the cell wall or to other pilin subunits. The molecular basis of transpeptidation and sorting signal recognition are not well understood, because the intermediates of catalysis are short lived. We have overcome this problem by synthesizing an analog of the LPXTG signal whose stable covalent complex with the enzyme mimics a key thioacyl catalytic intermediate. Here we report the solution structure and dynamics of its covalent complex with the Staphylococcus aureus SrtA sortase. In marked contrast to a previously reported crystal structure, we show that SrtA adaptively recognizes the LPXTG sorting signal by closing and immobilizing an active site loop. We have also used chemical shift mapping experiments to localize the binding site for the triglycine portion of lipid II, the second substrate to which surface proteins are attached. We propose a unified model of the transpeptidation reaction that explains the functions of key active site residues. Since the sortase-catalyzed anchoring reaction is required for the virulence of a number of bacterial pathogens, the results presented here may facilitate the development of new anti-infective agents.Bacterial surface proteins function as virulence factors that enable pathogens to adhere to sites of infection, evade the immune response, acquire essential nutrients, and enter host cells (1). Gram-positive bacteria use a common mechanism to covalently attach proteins to the cell wall. This process is catalyzed by sortase transpeptidase enzymes, which join proteins bearing a highly conserved Leu-Pro-X-Thr-Gly (LPXTG, where X is any amino acid) sorting signal to the cross-bridge peptide of the peptidylglycan (2-4). Sortases also polymerize proteins containing sorting signals into pili, filamentous surface exposed structures that promote bacterial adhesion (5, 6). The search for small molecule sortase inhibitors is an active area of research, since these enzymes contribute to the virulence of a number of important pathogens, including among others Staphylococcus aureus, Listeria monocytogenes, Streptococcus pyogenes, and Streptococcus pneumoniae (reviewed in Refs. 7 and 8). Sortase enzymes are also promising molecular biology reagents that can be used to site-specifically attach proteins to a variety of biomolecules (9 -14, 72).The sortase A (SrtA) 7 enzyme from S. aureus is the prototypical member of the sortase enzyme family (15, 16). It anchors proteins to the murein sacculus that possess a COOH-terminal cell wall sorting signal that consists of a LPXTG motif, followed by a hydrophobic segment of amino acids and a tail composed of mostly positively charged residues (17). SrtA is located on the extracellular side of the membrane. After partial secretion of its protein substrate across the cell membrane, SrtA cleaves the LPXTG motif between...

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“…The approximately 100-residue ARID sequence is present in a series of proteins strongly implicated in the regulation of cell growth, development, and tissue-specific gene expression. Although about a dozen ARID-containing proteins can be identified from database searches, to date, only Bright (a regulator of Bcell-specific gene expression), dead ringer (a Drosophila melanogaster gene product required for normal development), and MRF-2 (which represses expression from the cytomegalovirus enhancer) have been analyzed directly in regard to their DNA binding properties (Herrscher et al 1995;Iwahara et al 2002;Yuan et al 1998). Each binds preferentially to AT-rich sites.…”

mentioning

confidence: 99%

Backbone and sidechain 1H, 13C and 15N resonance assignments of the Bright/ARID domain from the human JARID1C (SMCX) protein

et al. 2007

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The structure of the Dead ringer-DNA complex reveals how AT-rich interaction domains (ARIDs) recognize DNA

Cited by 64 publications

References 82 publications

Mutations in the DNA-binding Domain of the Transcription Factor Bright Act as Dominant Negative Proteins and Interfere with Immunoglobulin Transactivation

Mutations in the DNA-binding Domain of the Transcription Factor Bright Act as Dominant Negative Proteins and Interfere with Immunoglobulin Transactivation

The Structure of the Staphylococcus aureus Sortase-Substrate Complex Reveals How the Universally Conserved LPXTG Sorting Signal Is Recognized

Backbone and sidechain 1H, 13C and 15N resonance assignments of the Bright/ARID domain from the human JARID1C (SMCX) protein

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