Allosteric control of metal-responsive transcriptional regulators in bacteria

Abstract

Many transition metals are essential trace nutrients for living organisms, but they are also cytotoxic in high concentrations. Bacteria maintain the delicate balance between metal starvation and toxicity through a complex network of metal homeostasis pathways. These systems are coordinated by the activities of metal-responsive transcription factors—also known as metal-sensor proteins or metalloregulators—that are tuned to sense the bioavailability of specific metals in the cell in order to regulate the expression of genes encoding proteins that contribute to metal homeostasis. Metal binding to a metalloregulator allosterically influences its ability to bind specific DNA sequences through a variety of intricate mechanisms that lie on a continuum between large conformational changes and subtle changes in internal dynamics. This review summarizes recent advances in our understanding of how metal sensor proteins respond to intracellular metal concentrations. In particular, we highlight the allosteric mechanisms used for metal-responsive regulation of several prokaryotic single-component metalloregulators, and we briefly discuss current open questions of how metalloregulators function in bacterial cells. Understanding the regulation and function of metal-responsive transcription factors is a fundamental aspect of metallobiochemistry and is important for gaining insights into bacterial growth and virulence.

Allosteric regulation of the nickel-responsive NikR transcription factor from Helicobacter pylori

“…The limited availability and inherent toxicity of nickel mean that maintaining desirable levels of this metal necessitates an extensive network of nickel acquisition, storage, delivery, and efflux pathways ( 9 , 12 , 13 , 14 , 15 ). In many organisms that utilize nickel, these systems are coordinated by the nickel-responsive transcription factor NikR, which is referred to as a metalloregulator or metal-sensor protein ( 16 , 17 , 18 , 19 ). In H. pylori , NikR (HpNikR) senses the bioavailability of nickel and subsequently activates or represses transcription of a variety of genes encoding nickel homeostasis proteins and acid adaptation factors, including the urease enzyme precursor proteins ( 17 , 18 , 20 , 21 , 22 , 23 ).…”

“…HpNikR binds an oligonucleotide recognition sequence in the promoter of target genes that consists of two half sites that are a pseudo-symmetric palindrome separated by a spacer ( 24 , 25 , 26 , 27 ). Binding nickel allosterically activates complex formation with this DNA recognition sequence, resulting in transcriptional regulation ( 16 , 28 , 29 , 30 , 31 ). HpNikR-regulated promoters have a weak consensus sequence ( 24 , 26 ) and are roughly divided into two tiers based on whether they are bound by HpNikR with affinities in the nanomolar or micromolar range ( 25 ).…”

Transcriptional and translational responsiveness of theNeisseria gonorrhoeaetype IV secretion system to conditions of host infections

“…The mechanism of toxicity for copper and zinc is often mismetallation of proteins (Sheldon and Skaar 2019; Baksh and Zamble 2020). Since Fur is an active regulator in this system, we performed β-galactosidase assays to determine whether the effects of zinc and copper on TraD expression were a result of Fur mismetallation.…”

“…Zinc and copper could be acting at a number of points in the regulatory network: they could enhance TraD protein stability, perhaps by inhibiting the activity of a protease or by activating a chaperone protein for TraD, or they could act upon another regulator within this system, potentially one that is also controlled by iron-dependent Fur regulation. (Baksh and Zamble 2020) (Figure 8).…”

Cu Homeostasis in Bacteria: The Ins and Outs

“…Metal-sensing transcriptional regulators are typically homo-oligomeric (dimeric or tetrameric) DNA-binding proteins that undergo an allosteric transition when bound to their cognate metal [ 292 ]. They usually follow a common organization in which the N-terminal DNA-binding domain (DBD) is followed by a C-terminal metal-binding domain (MBD).…”