Introduction
Tuberculosis, caused by Mycobacterium tuberculosis, is a respiratory infection still prevalent throughout the world. During the last decade, the emergence of multi-drug resistant strains of M. tuberculosis has given rise to the need for the development of new antibiotics in order to combat the infection. In order to develop an efficacious antibiotic, the drug must be able to target a unique aspect of the bacteria, such as a protein, that is critical for its full virulence and survival. MgtC, an integral protein embedded in the extracellular membrane of M. tuberculosis, has recently been hypothesized as a novel drug target to resolve tuberculosis infections. The targeting of MgtC was a result of observing that upon deletion of the protein from M. tuberculosis, the bacteria are no longer able to survive.
Structure
Based on its tertiary structure, this protein has been placed into a larger group of proteins known as the MgtC superfamily. The overall structure of MgtC is constituted by two domains: an N-terminal domain and a C-terminal domain. Each of these domains have striking similarities and differences with other MgtC-like proteins.
N-terminal Domain
The N-terminal domain of MgtC is highly-conserved between orthologues of the MgtC super family. This domain is largely hydrophobic and serves as the main component of MgtC that allows its embedment in the extracellular membrane. While this domain is highly conserved amongst orthologues, a crystal structure is not yet available.
C-terminal Domain
This domain of MgtC, in contrast, is highly variable in comparison to several orthologues, as presented by Yang et al. While the N-terminal domain is largely hydrophobic, this domain is relatively hydrophilic and soluble. Additionally, there is a crystal structure available for this domain. When comparing the crystal structure of the C-terminal domain to other protein structures, there are striking similarities between this domain and a class of proteins known as ACT domains.
Function
Collectively, because there is not a crystal structure available for the entire protein and the high variability of the C-terminal domain, it has been difficult to characterize the biochemical function performed by MgtC within M. tuberculosis. Several roles have been proposed, including magnesium uptake, the binding of amino acids, and chelation.
Magnesium Transport
A role for MgtC as a magnesium transporter has been debated since its discovery. Several publications have produced data indicating that this protein is critical for the uptake of magnesium in magnesium-deprived medium, while other literature has shown that this protein plays an insignificant role in this process.
Support for a role in magnesium transport is supported by: 1) Mutants of MgtC are unable to survive in low-magnesium environment; 2) Expression of the gene encoding for MgtC is highly-induced in low magnesium environment; 3) Genes adjacent to the MgtC gene encode for known magnesium transporters. Very recent evidence against MgtC playing a role in magnesium transport showed that RT-PCR experiments gave consistent levels of MgtC expression despite changes in the concentration of extracellular magnesium.
Potential for Binding Amino Acids
The exploration of this role for MgtC was first considered because of the ACT domain-like structure of the C-terminal domain. ACT domains commonly bind small amino acids within the cell as a form of regulation. Yang et al. showed that the structure of the C-terminal domain overlaps significantly with the structure of SerA, a known amino acid-binding ACT domain from E. coli. However, the glycine that is critical for the binding of amino acids in these ACT domains has been substituted in MgtC with a tyrosine, likely abolishing any potential amino acid binding activity
Disease
Relevance
Structural highlights
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