Nickel Homeostasis: Mechanism and function ofNikR

Abstract

Nickel plays an important role in many organisms as a cofactor of enzyme active sites. However, nickel ions can be toxic and therefore require a robust regulation system. Found in a wide variety of bacteria and archaea, NikR is a transcription factor that regulates intracellular nickel homeostasis. The activities of NikR homologs from several microorganisms have been examined in detail both in vitro and in vivo. Ni 2+ loading promotes DNA binding by NikR , an activity supplemented by additional, homolog‐specific cation requirements. Furthermore, there is evidence that the mechanism of nickel‐activated DNA binding includes stabilization of secondary structural elements of the protein that promote the formation of nonspecific DNA contacts. Although a key function of NikR is to regulate nickel uptake, the extent of its influence and its connection with other cellular pathways varies between organisms. Common features and contrasting activities within NikR homologs are presented and major outstanding questions are described.

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

“…The cis state has only been observed in the crystal structure of Ni(II)-EcNikR in complex with DNA ( 38 ). Although Trp54 is not conserved in EcNikR, published sequence alignments of NikR homologs reveal that it corresponds to Thr45 ( 17 , 32 , 40 ), all four of which are resolved in the structure of the Ni(II)–EcNikR–DNA complex ( 38 ). Two of the Thr45 residues appear to be solvent-exposed, while the other two are more buried, similar to the environments observed for the tryptophan residues in the trans state of HpNikR and PhNikR.…”

“…Nickel is an essential nutrient for the survival of H. pylori in the human stomach ( 6 ). HpNikR maintains the balance between nickel starvation and toxicity by activating or repressing the transcription of genes encoding proteins involved in nickel storage, utilization, and transport ( 17 , 19 , 23 ). However, HpNikR can also regulate a variety of other genes, such as those involved in acid adaptation, and is considered a “master regulator” in H. pylori ( 17 , 20 , 21 , 22 , 23 , 31 ).…”

“…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 ).…”

“…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 ).…”

“…However, crystal structures of NikR without DNA reveal the open and trans conformers, regardless of nickel binding, suggesting that nickel alone does not induce a conformational shift or large changes in tertiary structure ( 32 , 37 , 39 , 40 ). In EcNikR, nickel binding has been shown to induce short-range effects in the MBD to allosterically activate DNA binding, but there is no evidence to support the same type of mechanism in HpNikR ( 16 , 17 ). Instead, allostery in HpNikR is believed to be driven by changes in dynamics, specifically the mobility of the DBDs ( 16 , 45 , 46 , 47 ).…”