CBS domains: Ligand binding sites and conformational variability

Ereño‐Orbea, June; Oyenarte, Iker; Martínez-Cruz, Luis Alfonso

doi:10.1016/j.abb.2013.10.008

Cited by 120 publications

(165 citation statements)

References 61 publications

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“…S2) (22). Flat disk-like dimers represent the most frequent association manner of Bateman modules (12,13). We should mention, however, that, in our crystals, the CBS module of hCBS E201S appears slightly tilted (∼40 degrees) with respect to the surface of the protein cores compared with dCBS (Fig.…”

Section: Structure Of Activated Hcbsmentioning

confidence: 81%

“…Finally, the C-terminal region consists of a tandem pair of CBS motifs (7)(8)(9) that bind S-adenosylmethionine (AdoMet) and lead to an increase in catalytic activity by up to fivefold (10,11). The CBS motif pair, commonly known as a "Bateman module" (12,13), is responsible for CBS subunit tetramerization (14,15). The presence of pathogenic missense mutations in this region often does not impair enzyme activity but typically interferes with binding of AdoMet and/or the enzyme's activation by AdoMet (15)(16)(17).…”

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confidence: 99%

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Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S -adenosylmethionine

Ereño‐Orbea

Majtán

Oyenarte

et al. 2014

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

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Significance Cystathionine β-synthase (CBS), the pivotal enzyme of the transsulfuration pathway, regulates flux through the pathway to yield compounds, such as cysteine, glutathione, taurine, and H 2 S, that control cellular redox status and signaling. Our crystal structure of an engineered human CBS construct bound to S -adenosylmethionine (AdoMet) reveals the unique binding site of the allosteric activator and the architecture of the human CBS enzyme in its activated conformation. Together with the basal conformation that we reported earlier, these structures unravel the molecular mechanism of human CBS activation by AdoMet. Current knowledge will allow for modeling of numerous pathogenic mutations causing inherited homocystinuria and for design of compounds modulating CBS activity.

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Section: Structure Of Activated Hcbsmentioning

confidence: 81%

mentioning

confidence: 99%

Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S -adenosylmethionine

Ereño‐Orbea

Majtán

Oyenarte

et al. 2014

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

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150

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“…Bateman domains are found in proteins from all kingdoms of life, play critical cellular regulatory roles, and when mutated cause diverse and serious diseases, including homocystinuria, hypertrophic cardiomyopathy, and retinitis pigmentosa (18)(19)(20)(21). Bateman domains interact with diverse regulatory ligands, including adenosine nucleosides (18), cytoplasmic ions (22), charged membrane domains (23), DNA and RNA (24,25), and other proteins (26).…”

Section: Introductionmentioning

confidence: 99%

“…Bateman domains interact with diverse regulatory ligands, including adenosine nucleosides (18), cytoplasmic ions (22), charged membrane domains (23), DNA and RNA (24,25), and other proteins (26). Interactions with regulatory ligands induce Bateman domain conformational changes that control protein function (19,21).…”

Section: Introductionmentioning

confidence: 99%

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

Yamada

Krzeminski

Bozóky

et al. 2016

Biophysical Journal

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Eukaryotic CLC anion channels and transporters are homodimeric proteins composed of multiple a-helical membrane domains and large cytoplasmic C-termini containing two cystathionine-b-synthase domains (CBS1 and CBS2) that dimerize to form a Bateman domain. The Bateman domains of adjacent CLC subunits interact to form a Bateman domain dimer. The functions of CLC CBS and Bateman domains are poorly understood. We utilized the Caenorhabditis elegans CLC-1/2/Ka/ Kb anion channel homolog CLH-3b to characterize the regulatory roles of CLC cytoplasmic domains. CLH-3b activity is reduced by phosphorylation or deletion of a 14-amino-acid activation domain (AD) located on the linker connecting CBS1 and CBS2. We demonstrate here that phosphorylation-dependent reductions in channel activity require an intact Bateman domain dimer and concomitant phosphorylation or deletion of both ADs. Regulation of a CLH-3b AD deletion mutant is reconstituted by intracellular perfusion with recombinant 14-amino-acid AD peptides. The sulfhydryl reactive reagent 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET) alters in a phosphorylation-dependent manner the activity of channels containing single cysteine residues that are engineered into the short intracellular loop connecting membrane a-helices H and I (H-I loop), the AD, CBS1, and CBS2. In contrast, MTSET has no effect on channels in which cysteine residues are engineered into intracellular regions that are dispensable for regulation. These studies together with our previous work suggest that binding and unbinding of the AD to the Bateman domain dimer induces conformational changes that are transduced to channel membrane domains via the H-I loop. Our findings provide new, to our knowledge, insights into the roles of CLC Bateman domains and the structurefunction relationships that govern the regulation of CLC protein activity by diverse ligands and signaling pathways.

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“…Finally, the predicted DhcR regulons include multiple hypothetical genes, including at least four orthologous groups of genes encoding CBS domain proteins ( Table 2). The CBS domain (PF00571) is a protein domain found in a wide variety of proteins, where it plays a regulatory role in the activity of associated enzymatic domains in response to various ligands (34). This could suggest a potential role of DhcR-regulated CBS domain proteins as regulators associated with autotrophic carbon dioxide fixation cycle enzyme activities.…”

Section: Experimental Validation Of Hhcr Regulons In Metallosphaera Smentioning

confidence: 99%

Novel Transcriptional Regulons for Autotrophic Cycle Genes in Crenarchaeota

Leyn

Rodionova

et al. 2015

J Bacteriol

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Autotrophic microorganisms are able to utilize carbon dioxide as their only carbon source, or, alternatively, many of them can grow heterotrophically on organics. Different variants of autotrophic pathways have been identified in various lineages of the phylum Crenarchaeota. Aerobic members of the order Sulfolobales utilize the hydroxypropionate-hydroxybutyrate cycle (HHC) to fix inorganic carbon, whereas anaerobic Thermoproteales use the dicarboxylate-hydroxybutyrate cycle (DHC). Knowledge of transcriptional regulation of autotrophic pathways in Archaea is limited. We applied a comparative genomics approach to predict novel autotrophic regulons in the Crenarchaeota. We report identification of two novel DNA motifs associated with the autotrophic pathway genes in the Sulfolobales (HHC box) and Thermoproteales (DHC box). Based on genome context evidence, the HHC box regulon was attributed to a novel transcription factor from the TrmB family named HhcR. Orthologs of HhcR are present in all Sulfolobales genomes but were not found in other lineages. A predicted HHC box regulatory motif was confirmed by in vitro binding assays with the recombinant HhcR protein from Metallosphaera yellowstonensis. For the DHC box regulon, we assigned a different potential regulator, named DhcR, which is restricted to the order Thermoproteales. DhcR in Thermoproteus neutrophilus (Tneu_0751) was previously identified as a DNA-binding protein with high affinity for the promoter regions of two autotrophic operons. The global HhcR and DhcR regulons reconstructed by comparative genomics were reconciled with available omics data in Metallosphaera and Thermoproteus spp. The identified regulons constitute two novel mechanisms for transcriptional control of autotrophic pathways in the Crenarchaeota. IMPORTANCELittle is known about transcriptional regulation of carbon dioxide fixation pathways in Archaea. We previously applied the comparative genomics approach for reconstruction of DtxR family regulons in diverse lineages of Archaea. Here, we utilize similar computational approaches to identify novel regulatory motifs for genes that are autotrophically induced in microorganisms from two lineages of Crenarchaeota and to reconstruct the respective regulons. The predicted novel regulons in archaeal genomes control the majority of autotrophic pathway genes and also other carbon and energy metabolism genes. The HhcR regulon was experimentally validated by DNA-binding assays in Metallosphaera spp. Novel regulons described for the first time in this work provide a basis for understanding the mechanisms of transcriptional regulation of autotrophic pathways in Archaea. The Thermoproteales and Sulfolobales are two groups of thermophilic archaea from the phylum Crenarchaeota. Members of both groups can grow under autotrophic conditions by using carbon dioxide as a carbon source (1, 2). Studies of model organisms revealed the presence of two distinct autotrophic carbon dioxide fixation pathways in these crenarchaeal lineages (3-12). Thermoproteus ne...

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CBS domains: Ligand binding sites and conformational variability

Cited by 120 publications

References 61 publications

Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S -adenosylmethionine

Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S -adenosylmethionine

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

Novel Transcriptional Regulons for Autotrophic Cycle Genes in Crenarchaeota

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