Crystal Structure of Mycobacterium tuberculosis H37Rv AldR (Rv2779c), a Regulator of the ald Gene

Abstract

Feast/famine regulatory proteins (FFRPs), 5 also known as Lrp/AsnC family proteins, bind to a variety of effectors like amino acids that modulate the respective regulatory functions. They are involved in the formation of globular nucleoprotein structures, chromosome structure organization, and other regulatory functions (1). Directly or indirectly, they globally regulate a variety of metabolic processes in response to amino acids and nitrogen bases present in the environment. The general understanding is that FFRPs adopt a variety of quaternary structures upon binding/release of effectors. This presumably allows for binding to target promoter regions or for disrupting the nucleoprotein structures formed by them (2). Fine tuning/ selection of the target promoter-FFRP interactions is also generally thought to occur due to binding of the effector molecules and in some cases can elicit subtle structural changes as opposed to changes to the oligomeric association itself (3, 4). Escherichia coli Lrp, a better studied member of the family, is known to be important for changes that occur from a "feasting" to a "famine" state, and it controls ϳ10% of gene expression (5, 6). The latter protein binds to a variety of amino acids like Leu, Ala, Pro, and Val, and that in turn elicits either positive or negative regulation of the target genes (7).Crystal structures of several FFRPs/Lrp/AsnC-type proteins have been reported from bacterial and archaeal sources. These include structures of the E. coli Lrp, E. coli AsnC, Mycobacterium tuberculosis FFRP (also called LrpA), Lrp proteins from Pyrococcus furiosus, and Pyrococcus sp. OT3 FL11. Complexes of some of them with several amino acids, DNA, etc. have also been reported (8 -10). The studies reveal that the basic functional unit of FFRPs is a dimer where each chain folds into two domains. The N-terminal domain normally faces outside and contains the DNA-binding helix-turn-helix motif and a C-terminal domain that is involved in effector binding and in oligomerization. Both of the domains are connected by a rather long linker region. Some FFRPs like the M. tuberculosis FFRP and E. coli Lrp have been shown to adopt the rare "open" quaternary structure that seems to be an operating principle in these proteins. This presumably allows them to bind to non-symmetrical target sites (10 -12). In general, instances of deviations from oligomeric symmetry in proteins are rare, and wherever they are observed, it is attributed to strong functional reasons (13). Helical cylindrical arrangements are the other kind of assembly observed in P. furiosus sp. OT3 Lrp. FFRPs may have one or more types of effector binding sites (e.g. E. coli AsnC has one binding site, whereas those like M. tuberculosis FFRP have at least two types of binding sites, each with different hypothesized roles) (8). The type I binding site is a common site in the FFRP family that occurs at the interdimer interface at the C-terminal oligomerization domain, whereas the type II site was identified in M. tuberculosis FFRP at the i...

Feeding on compatible solutes: A substrate‐induced pathway for uptake and catabolism of ectoines and its genetic control by EnuR

“…E). This observation suggests an important regulatory function of the “feast and famine”‐type AsnC transcriptional regulator (Kumarevel et al, ; Deng et al, ; Dey et al, ) for the expression of the 5‐hydroxyectoine/ectoine uptake and catabolic gene cluster of R. pomeroyi .…”

“…A) encodes a regulatory protein belonging to the “feast and famine” family of transcriptional regulators (Deng et al, ). These types of regulatory proteins often form octamers wrapping the target DNA around them and their DNA‐binding properties are dictated by small molecules, mostly amino acids (e.g., l ‐Leucine, l ‐Glutamine, l ‐Alanine, l ‐Tyrosine, l ‐Tryptophane, or l ‐Aspartate) (Kumarevel et al, ; Dey et al, ).…”

“…AsnC‐type regulators belong to the “feast and famine” group of transcriptional regulators (Deng et al, ). They form oligomers (often octamers) wrapping the target DNA around them and their DNA‐binding properties are dictated by small molecules, mostly amino acids (Kumarevel et al, ; Deng et al, ; Dey et al, ). An asnC ‐type gene ( deoX ) is also present in the ectoine catabolic gene cluster of H. elongata (Fig.…”

Transcriptional regulation of ectoine catabolism in response to multiple metabolic and environmental cues

“…AsnC exerts a clear activating influence on the expression of the R. pomeroyi hydroxyectoine/ectoine-importer and catabolic gene cluster. AsnC/Lrp-type proteins wrap DNA into nucleosome-like structures and frequently respond in their DNA-binding properties to low-molecularmass effector molecules that are generated through metabolism (e.g., amino acids) (Shrivastava and Ramachandran, 2007;Kumarevel et al, 2008;Dey et al, 2016). In many cases, these proteins respond to feast-and-famine situations and thereby permit the efficient exploitation of sudden burst in the supply of a particular nutrient in fluctuating environmental settings (Yokoyama et al, 2006).…”

“…S3). These types of proteins can form octamers wrapping their target DNA around them into a high-ordered tertiary nucleosome-like complex, and their DNA-binding properties are dictated through interactions with low-molecular-mass effector molecules, often amino acids (Yokoyama et al, 2006;Shrivastava and Ramachandran, 2007;Kumarevel et al, 2008;Kamensek et al, 2015;Dey et al, 2016). We have previously demonstrated that the deletion of the last two genes (ssd-atf) in the hydroxyectoine/ectoine catabolic operon (Fig.…”