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==MgtC: A Virulence Factor From ''Mycobacterium tuberculosis''==
==Your Protein Name here==
<StructureSection load='2lqj' size='340' side='right' caption='C-terminal Domain of Mg2+ transport P-type ATPase C (PDB: [http://www.rcsb.org/pdb/explore.do?structureId=2lqj 2LQJ])' scene='69/698113/Rainbow-colored_spectrum/2'>
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
==Introduction==
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
[http://en.wikipedia.org/wiki/Tuberculosis Tuberculosis], caused by ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]'', is a [http://en.wikipedia.org/wiki/Respiratory_tract_infection respiratory infection] still prevalent throughout the world.  During the last decade, the emergence of [http://en.wikipedia.org/wiki/Multiple_drug_resistance multi-drug resistant] strains of ''M. tuberculosis'' has given rise to the need for the development of new [http://en.wikipedia.org/wiki/Antibiotics antibiotics] in order to combat the infection<ref>Singh, G.; Singh, G.; Jadeja, D.; Kaur, J.  Lipid hydrolyzing enzymes in virulence: Mycobacterium tuberculosis as a model system.  Critical Reviews in Microbiology 2010, 36(3): 259-269. DOI: 10.3109/1040841X.2010.482923.</ref>.  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 [http://en.wikipedia.org/wiki/Integral_membrane_protein 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 due to inhibition of  [http://en.wiktionary.org/wiki/intramacrophage intramacrophage] growth. <ref name="mgtc">Yang, Y.; Labesse, G.; Carrere-Kremer, S.; Esteves, K.; Kremer, L.; Cohen-Gonsaud, M.; Blanc-Potard, A.  The C-terminal domain of the virulence factor mgtc is a divergent act domain.  J Bacteriol. 2012, 194(22): 6255-6263. DOI: 10.1128/JB.01424-12.</ref>.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
== Structure ==
Based on its [http://en.wikipedia.org/wiki/Protein_tertiary_structure tertiary structure], this protein has been placed into a larger group of proteins known as the [http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=120498 MgtC superfamily].  The overall structure of MgtC is constituted by two [http://en.wikipedia.org/wiki/Protein_domain domains]:  an N-terminal domain and a C-terminal domain.  Each of these domains have striking similarities and differences with other MgtC-like proteins.<ref name="mgtc"/>


===N-terminal Domain===
== Biological Function ==
The N-terminal domain of MgtC is highly-conserved between [http://en.wiktionary.org/wiki/orthologue orthologs] of the MgtC [http://en.wikipedia.org/wiki/Protein_superfamily 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 among orthologs, a [http://en.wikipedia.org/wiki/Crystal_structure crystal structure] is not yet available, but the sequence available has determined it to be largely hydrophobic. <ref name="mgtc"/>


===C-terminal Domain===
== Structural Overview ==
This domain of MgtC, in contrast, is highly variable in comparison to several orthologs, as presented by Yang ''et al''. However, it is this <scene name='69/698113/Secondary_structured_coloring/2'>tertiary structure</scene> containing two α-helices and four anti-parallel β-sheets that is incredibly indicative of the MgtC super family. Through a sequence alignment of five known functional MgtC orthologs from [http://en.wikipedia.org/wiki/Pathogen pathogens] that survive inside [http://en.wikipedia.org/wiki/Macrophage macrophages] (''M. tuberculosis, [http://en.wikipedia.org/wiki/Brucella_melitensis B. melitensis], [http://en.wikipedia.org/wiki/Burkholderia_cenocepacia B. cenocepacia], [http://en.wikipedia.org/wiki/Yersinia_pestis Y. pestis],'' and ''[http://en.wikipedia.org/wiki/Salmonella_enterica_subsp._enterica S. Typhimurium]''), seven strictly conserved residues were found to be scattered along the whole sequence of the relatively hydrophilic and soluble C-terminal domain. <ref name="mgtc"/>


A large hydrophobic core has conserved residues <scene name='69/698113/Colored_core_residues/6'>Cysteine-155, Arginine-164, Glutamine-160, and Alanine-195</scene>.
== Mechanism of Action ==


[[Image:Final_Final_Core_Logo.PNG |625× 116px|thumb|left|Four strictly conserved residues of five known functional MgtC orthologs of the soluble C-terminal domain.
== Zinc Ligand(s) ==
The figure was prepared using WebLogo. (http://weblogo.berkeley.edu/)]]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The opposite side of the protein has a small cluster of conserved residues <scene name='69/698113/Conserved_surface_residues/6'>Tyrosine-149, Glutamine-208, and Tryptophan-225</scene>.
 
[[Image:Final_Surface_Web_Logo.PNG |625× 121px|thumb|left|Four strictly conserved residues of five known functional MgtC orthologs of the soluble C-terminal domain. The figure was prepared using WebLogo. (http://weblogo.berkeley.edu/)]]
 
 
 
 
 
 
 
 
 
 
 
 
 
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 [http://en.wikipedia.org/wiki/ACT_domain ACT domains]. <ref name="mgtc"/>
 
==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 metals, as well as facilitating dimerization with various proteins. <ref name="mgtc"/>
 
===Magnesium Transport===
A role for MgtC as a [http://en.wikipedia.org/wiki/Magnesium_transporter 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. <ref name="mgtc"/> <ref>Blanc-Potard, A.B.; Lafay, B.  MgtC as a horizontally-acquired virulence factor of intracellular bacterial pathogens : evidence from molecular phylogeny and comparative genomics.  J Mol Evol. 2003, 57(4): 479-86. DOI:  10.1007/s00239-003-2496-4 </ref> <ref>Belon, C.; Gannoun-Zaki, L.; Lutfalla, G.; Kremer, L.; Blanc-Potard, A.B.  Mycobacterium marinum mgtc plays a role in phagocytosis but is dispensable for intracellular multiplication.  Plos One 2014, 1-23. DOI: 10.1371/journal.pone.0116052. </ref>
 
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  [http://en.wikipedia.org/wiki/Reverse_transcription_polymerase_chain_reaction RT-PCR] experiments gave consistent levels of MgtC expression despite changes in the concentration of extracellular magnesium. <ref name="mgtc"/>
 
===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 [http://geneontology.org/page/regulation regulation]. Yang ''et al''. showed that the structure of the C-terminal domain overlaps significantly with the structure of [http://proteopedia.org/wiki/index.php/1psd SerA] (PDB: [http://www.rcsb.org/pdb/explore/explore.do?structureId=1psd 1PSD]), a known amino acid-binding ACT domain from ''[http://www.cdc.gov/ecoli/ E. coli]''.  '''Figure 1A''' shows the overlap of these two proteins; the cyan protein represents MgtC and the orange protein represents SerA. However, the glycine that is critical for the binding of amino acids in these ACT domains has been substituted in MgtC with a <scene name='69/698113/Sub_residues_of_sera/2'>tyrosine</scene>, likely abolishing any potential amino acid binding activity <ref name="mgtc"/>
 
===Potential for Chelation===
As with the potential for binding amino acids, this role was also explored because of the structural similarity of the C-terminal domain with ACT domains, as ACT domains also serve as excellent [http://en.wikipedia.org/wiki/Chelation chelators] to sequester cations within the cell.  Yang ''et al''. also compared the structure of the C-terminal domain of MgtC with an ACT domain of a known chelator, [http://proteopedia.org/wiki/index.php/3lgh NikR] (PDB: [http://www.rcsb.org/pdb/explore/explore.do?structureId=3LGH 3LGH]).  These structures overlapped quite well, indicating that MgtC may serve as a chelator.  '''Figure 1B''' highlights the significant overlap between these residues; the cyan protein represents MgtC and the orange protein represents NikR.  However, the two histidine residues and the cysteine residue present in NikR that serve as the chelating residues are modified to <scene name='69/698113/Sub_residues_of_chelat/3'>threonine, proline, and isoleucine</scene> respectively.  These substitutions likely prevent any chelating activity by MgtC. <ref name="mgtc"/>
[[Image:Combined_overlaps.png |458 x 210 px|thumb|center|'''Figure 1.  Overlap of the C-terminal Domain of MgtC with ACT domains of known function.''' 1A shows the significant overlap of the C-terminal of MgtC with SerA, an ACT domain that has been established to bind amino acids.  1B shows the overlap of the C-terminal domain of MgtC with NikR, a known chelating ACT domain.]]
 
===Role in Dimerization===
The potential for [http://en.wikipedia.org/wiki/Protein_dimer dimerization] was another aspect of MgtC studied to see if this protein forms complexes with proteins of known function.  A [http://subtiwiki.uni-goettingen.de/wiki/index.php/BACTH Bacterial Two-Hybrid (BACTH)] assay was performed to study the potential for the entire protein to dimerize with itself and the potential for individual domains to dimerize.  The results of this assay showed that the entire MgtC protein likely dimerizes, but the individual domains do not.  This dimerization could serve as a critical component to the biochemical function of MgtC, although the exact implications have not yet been discerned <ref name="mgtc"/>.  Frantz ''et al''. proposed a role for MgtC to form dimers with [http://proteopedia.org/wiki/index.php/2mc7 MgtR] (PDB: [http://www.rcsb.org/pdb/explore/explore.do?structureId=2MC7 2MC7]), a protein that serves to promote the degradation of MgtC.<ref name="mgtr">Jean-Francois, F.L.; Dai, J.; Yu, L. ; Myrick, A. ; Rubin, E. ; ''et al''.  Binding of mgtr, a salmonella transmembrane regulatory peptide, to mgtc, a mycobacterium tuberculosis virulence factor:  a structural study. DOI:10.1016/j.jmb.2013.10.014</ref>  This has huge implications in the overall clinical relevance of how MgtC could be targeted to develop new-generation antibiotics.
 
==Clinical Relevance ==
The development of an antibiotic which targets and inhibits MgtC could come from exploitation and enhancement of the process which promotes its degradation within ''Mycobacterium tuberculosis.'' MgtR, a hydrophobic peptide, promotes the degradation of MgtC upon high expression within the bacteria.<ref name="mgtr"/>  As previously stated, inadequate levels of MgtC within ''M. tuberculosis'' results in an inability to grow and survive. <ref name="mgtr"/>  It is quite reasonable that analogues of MgtR could be developed, injected ([http://en.wikipedia.org/wiki/Subcutaneous_injection subcutaneously]) into infected patients, and resolve the tuberculosis infection by promoting degradation of MgtC and impairing growth of ''M. tuberculosis.''
 
==Future Work==
[[Image:Aligned 3.png|210 px|thumb|right|'''Figure 2.  Overlap of MgtC C-terminal domain with the ACT domain of a GTP pyrophosphokinase.'''  This figure demonstrates the significant overlap between the C-terminal domain of MgtC and the ACT domain of a GTP pyrophosphokinase.]]
Since so little is known about MgtC, future work should involve both crystallizing the entire MgtC protein and characterizing its biochemical function.  Because the sequence of amino acids in a protein dictates structure, and structure typically determines the protein's function, further sequencing and structural analysis should be performed with MgtC to discern its function.  Shown in '''Figure 2''' is an overlap of MgtC (cyan) with the ACT domain of a [http://en.wikipedia.org/wiki/GTP_diphosphokinase GTP pyrophosphokinase] (PDB: [http://www.rcsb.org/pdb/explore/explore.do?structureId=2kO1 2KO1]) shown in orange.  This overlap shows even more extensive similarity than the aforementioned SerA and NikR ACT domains.  Structural similarity analysis could aid in resolving the biochemical function of MgtC.


== Other Ligands ==


This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.


</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

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