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Crystal structure of CodY from Staphylococcus aureus with GTP and IleCrystal structure of CodY from Staphylococcus aureus with GTP and Ile
Structural highlights
FunctionCODY_STAA8 DNA-binding global transcriptional regulator which is involved in the adaptive response to starvation and acts by directly or indirectly controlling the expression of numerous genes in response to nutrient availability. During rapid exponential growth, CodY is highly active and represses genes whose products allow adaptation to nutrient depletion.[HAMAP-Rule:MF_00621][1] In S.aureus, targets include over 200 genes (PubMed:20363936, PubMed:27116338). Acts mainly as a repressor of genes involved in amino acid transport and metabolism, including the branched-chain amino acids (BCAAs) biosynthetic operon (PubMed:19251851, PubMed:20363936, PubMed:27116338, PubMed:29357354). Several genes involved in nucleotide synthesis and transport are activated (PubMed:19251851). Binds to a 21-bp conserved DNA motif, the CodY-binding site (PubMed:20363936). Additionally, in pathogenic bacteria, CodY also regulates virulence gene expression and provides a regulatory link between metabolism and pathogenesis (PubMed:18156263, PubMed:19251851, PubMed:20363936, PubMed:27116338, PubMed:29378891). Genes encoding virulence and defense factors are either up- or down-regulated by CodY (PubMed:19251851). Among others, is involved in the repression of the accessory gene regulator (agr), the hemolytic alpha-toxin (hla) gene, and the icaADBC operon, responsible for the production of polysaccharide intercellular adhesin (PIA), a major contributor to biofilm formation in S.aureus (PubMed:18156263, PubMed:19251851). Also regulates the expression of thermonuclease (nuc) via the Sae two-component system, by binding directly to the sae P1 promoter region and blocking the binding of the positive regulator SaeR (PubMed:27116338, PubMed:29378891). It restrains Sae-dependent production of leukocidins (PubMed:29378891). CodY also controls the sae locus indirectly through Agr and Rot-mediated repression of the sae P1 promoter (PubMed:29378891). The virulence genes regulated by CodY fall into three groups: one group is regulated directly by CodY, a second group is indirectly regulated by CodY, in particular through its repression of the agr and sae loci, and a third group is regulated in two ways, by direct repression and by repression via another regulator (PubMed:19251851, PubMed:20363936, PubMed:29378891). S.aureus may use CodY to limit host damage to only the most severe starvation conditions (PubMed:27116338). Modulation of central metabolism, virulence gene expression, and biofilm-associated genes to optimize growth on preferred carbon sources until starvation sets in may require coordinated action of CodY and the carbon catabolite protein A (CcpA), another global transcriptional regulator (PubMed:35735992).[2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedGTP and branched-chain amino acids (BCAAs) are metabolic sensors that are indispensable for the determination of the metabolic status of cells. However, their molecular sensing mechanism remains unclear. CodY is a unique global transcription regulator that recognizes GTP and BCAAs as specific signals and affects expression of more than 100 genes associated with metabolism. Herein, we report the first crystal structures of the full-length CodY complex with sensing molecules and describe their functional states. We observed two different oligomeric states of CodY: a dimeric complex of CodY from Staphylococcus aureus with the two metabolites GTP and isoleucine, and a tetrameric form (apo) of CodY from Bacillus cereus Notably, the tetrameric state shows in an auto-inhibitory manner by blocking the GTP-binding site, whereas the binding sites of GTP and isoleucine are clearly visible in the dimeric state. The GTP is located at a hinge site between the long helical region and the metabolite-binding site. Together, data from structural and electrophoretic mobility shift assay analyses improve understanding of how CodY senses GTP and operates as a DNA-binding protein and a pleiotropic transcription regulator. The structure of the pleiotropic transcription regulator CodY provides insight into its GTP-sensing mechanism.,Han AR, Kang HR, Son J, Kwon DH, Kim S, Lee WC, Song HK, Song MJ, Hwang KY Nucleic Acids Res. 2016 Sep 4. pii: gkw775. PMID:27596595[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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