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Adhesin Competence RegulatorAdhesin Competence Regulator

IntroductionIntroduction

 
3TGN space fill model. Blue and white representing symmetric monomers.

Adhesin Competence Regulator (AdcR) is a transcriptional regulator that controls the activation of over seventy genes within the bacteria Streptococcus pneumoniae[1]. Contrasting with other members of the multiple antibiotic resistance regulator (MarR) family, AdcR is metal dependent as the binding of Zinc causes conformational changes that permit AdcR to repress the transcription of high-affinity Zinc specific uptake transporters. Zinc plays a vital role in organism homeostasis acting as a co-factor and a regulator of enzymatic activity, however zinc can lead to cell toxicity and deficiency of other vital metals that are also necessary for protein function[2][3]. Given the many roles zinc plays in general homeostasis the importance of AdcR in Streptococcus pneumoniae can be understood provided its ability to regulate zinc transfer proteins within the bacteria.

 
Proteins 3BPX, 2FBK, 3KP5, and 2PFB (members of the MarR family) are pictured above.

Members of the MarR protein family conserve a number of features including a general triangular shape, a two fold pseudosymmetric homo dimer, and a wingled helix-turn-helix pattern. Consistent with AdcR's identity as a member of the MarR protein family, AdcR exhibits the triangular shape with the (wHTH) binding domain. This structure calls for multiple zinc binding sites that facilitate protein conformational change allowing for DNA binding and regulation through the wHTH domain.


Zn(II) Binding

Zinc-Dependent Transcriptional Regulator AdcR has on each of its two protomers and can bind a total of four Zn(II). is made up of the alpha helix 1, alpha helix 5, and the alpha helix 6. This domain is connected to the HTH winged domain with the long alpha helix 5. This dimerization domain connects to the DNA binding domain and together with the alpha 1 alpha 2 loop make up the [4]. Each protomer has one high affinity site (KZn1 = 10^12 M; pH 8) and one low affinity binding site (KZn2 = 10^7 M; pH 8)Cite error: Closing </ref> missing for <ref> tag. The color coding in the previous sentence represents the (), which is seen across the MarR family as a whole.

 
A charge map of AdcR shows the general triangular shape and the positive charged (blue) area on HTH domains

Helix-Turn-Helix Domain

The AdcR MarR transcriptional regulator's structure resembles the other proteins in the same family as mentioned before; however, the most notable differences are found in the winged helix-turn-helix (wHTH) motif that assists in binding DNA. The major groove of DNA is bound to the recognition helix while the wings grip onto the minor grooves of DNA. The charge map on the right highlights the positively charged areas, which stabilize the negatively charged backbone of DNA. Although AdcR is a highly alpha helical protein, the "wings" of the DNA binding domain consist of two anti parallel beta strands that are made up of several positively charged residues [5]. There is a wHTH domain on each monomer of the protein.

The domain is made up of the alpha 2 and alpha 4 helices along with anti-parallel beta sheets on each side. Only one monomer is shown. The recognition helix, or the alpha 4 helix, binds the major groove of DNA through hydrogen bonding and Van der Waals interactions between exposed bases [6]. The wings of the helix bind the minor groove of DNA while the other helices stabilize the DNA and Protein upon binding. The two anti parallel beta sheets contain several that stabilize this interaction between DNA.

3TGN

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Sanson M, Makthal N, Flores AR, Olsen RJ, Musser JM, Kumaraswami M. Adhesin competence repressor (AdcR) from Streptococcus pyogenes controls adaptive responses to zinc limitation and contributes to virulence. Nucleic Acids Res. 2015 Jan;43(1):418-32. doi: 10.1093/nar/gku1304. Epub 2014 Dec, 15. PMID:25510500 doi:http://dx.doi.org/10.1093/nar/gku1304
  2. ↑ Fraústo da Silva J, Williams R. The Biological Chemistry of Elements: The Inorganic Chemistry of Life. Second ed. Oxford University Press; Oxford: 2001.
  3. ↑ Ma Z, Jacobsen FE, Giedroc DP. Coordination chemistry of bacterial metal transport and sensing. Chem Rev. 2009 Oct;109(10):4644-81. doi: 10.1021/cr900077w. PMID:19788177 doi:http://dx.doi.org/10.1021/cr900077w
  4. ↑ Guerra AJ, Dann CE, Giedroc DP. Crystal Structure of the Zinc-Dependent MarR Family Transcriptional Regulator AdcR in the Zn(II)-Bound State. J Am Chem Soc. 2011 Nov 21. PMID:22085181 doi:10.1021/ja2080532
  5. ↑ Guerra AJ, Dann CE, Giedroc DP. Crystal Structure of the Zinc-Dependent MarR Family Transcriptional Regulator AdcR in the Zn(II)-Bound State. J Am Chem Soc. 2011 Nov 21. PMID:22085181 doi:10.1021/ja2080532
  6. ↑ Guerra AJ, Dann CE, Giedroc DP. Crystal Structure of the Zinc-Dependent MarR Family Transcriptional Regulator AdcR in the Zn(II)-Bound State. J Am Chem Soc. 2011 Nov 21. PMID:22085181 doi:10.1021/ja2080532

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