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Structural and functional basis of transcriptional regulation by TetR family protein CprB from S. coelicolor A3(2).

Bhukya H, Bhujbalrao R, Bitra A, Anand R - Nucleic Acids Res. (2014)

Bottom Line: Binding of the DNA results in the restructuring of the dimeric interface of CprB, inducing a pendulum-like motion of the helix-turn-helix motif that inserts into the major groove.Experiments performed on a subset of DNA sequences from Streptomyces coelicolor A3(2) suggest that CprB is most likely a pleiotropic regulator.Apart from serving as an autoregulator, it is potentially a part of a network of proteins that modulates the γ-butyrolactone synthesis and antibiotic regulation pathways in S. coelicolor A3(2).

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India IITB-Monash Research Academy, Mumbai 400076, Maharashtra, India.

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A model representing the changes induced upon DNA binding in the TetR-FTR protein, CprB. Two forms of protein are shown in the figure, apo form (A), and operator (DNA) bound form (B). The operator binding induces a twist in the dimeric interface of the homodimer and facilitates the snug fit of HTH motif in the major groove of the DNA. Intermonomeric disulfide bond is represented as yellow line and the DNA in cartoon model.
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Figure 8: A model representing the changes induced upon DNA binding in the TetR-FTR protein, CprB. Two forms of protein are shown in the figure, apo form (A), and operator (DNA) bound form (B). The operator binding induces a twist in the dimeric interface of the homodimer and facilitates the snug fit of HTH motif in the major groove of the DNA. Intermonomeric disulfide bond is represented as yellow line and the DNA in cartoon model.

Mentions: To map the various conformational states that the TetR-FTR class of transcription factors access, a comparison of the apo, ligand and DNA-bound forms of the available structures was performed. Analyses showed that a global twist along the dimeric motif occurs in each case upon DNA binding. This results in restructuring of several interactions across various regions of the protein with the effect being most pronounced at the dimeric interface. As reported here, for CprB, ∼10 hydrogen bonds were restructured (Supplementary Tables S2 and S3). Our analyses show that a similar scenario is also observed for other members like QacR (PDB entry: 1JT0), CgmR (PDB entry: 2YVH) and SimR (PDB entry: 3ZQL) proteins, where DNA binding induces a considerable rearrangement of the specific interactions and many new hydrogen bonds were formed across the interface in each case. In all these proteins, a concurrent coordinated shift that facilitates the insertion of the recognition helix into the major groove of the DNA is also observed (similar to that shown for CprB, Figure 2A). This overall motion in the structures upon DNA binding results in locking the protein in a conformationally favorable state toward accepting inducers by increasing the accessibility to the ligand-binding pocket. Hence, it can be concluded that conformational changes are facilitated through a pendulum-like rearrangement of the fluid dimeric interface (Figure 8). Each monomer rotates along the dimeric axis with the direction of rotation being determined so as to facilitate operator binding. These kinds of allosteric transitions that facilitate function are seen in various transcription factors that are regulated by small molecule inducers (25,60). For example, the well-established system, LacR, similar to TetR-FTRs, also adopts different conformations in the DNA, and the small molecule repressor (IPTG) bound forms; a subtle switch between these states controls its transcriptional activity (61). In contrast, there are also systems like the tetrameric gene regulator, TtgV, a multidrug-binding protein and controller of efflux pump, which undergo drastic conformational changes (like the wings of a flying bird) in structure between its operator and inducer-bound forms to assist function (62).


Structural and functional basis of transcriptional regulation by TetR family protein CprB from S. coelicolor A3(2).

Bhukya H, Bhujbalrao R, Bitra A, Anand R - Nucleic Acids Res. (2014)

A model representing the changes induced upon DNA binding in the TetR-FTR protein, CprB. Two forms of protein are shown in the figure, apo form (A), and operator (DNA) bound form (B). The operator binding induces a twist in the dimeric interface of the homodimer and facilitates the snug fit of HTH motif in the major groove of the DNA. Intermonomeric disulfide bond is represented as yellow line and the DNA in cartoon model.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150764&req=5

Figure 8: A model representing the changes induced upon DNA binding in the TetR-FTR protein, CprB. Two forms of protein are shown in the figure, apo form (A), and operator (DNA) bound form (B). The operator binding induces a twist in the dimeric interface of the homodimer and facilitates the snug fit of HTH motif in the major groove of the DNA. Intermonomeric disulfide bond is represented as yellow line and the DNA in cartoon model.
Mentions: To map the various conformational states that the TetR-FTR class of transcription factors access, a comparison of the apo, ligand and DNA-bound forms of the available structures was performed. Analyses showed that a global twist along the dimeric motif occurs in each case upon DNA binding. This results in restructuring of several interactions across various regions of the protein with the effect being most pronounced at the dimeric interface. As reported here, for CprB, ∼10 hydrogen bonds were restructured (Supplementary Tables S2 and S3). Our analyses show that a similar scenario is also observed for other members like QacR (PDB entry: 1JT0), CgmR (PDB entry: 2YVH) and SimR (PDB entry: 3ZQL) proteins, where DNA binding induces a considerable rearrangement of the specific interactions and many new hydrogen bonds were formed across the interface in each case. In all these proteins, a concurrent coordinated shift that facilitates the insertion of the recognition helix into the major groove of the DNA is also observed (similar to that shown for CprB, Figure 2A). This overall motion in the structures upon DNA binding results in locking the protein in a conformationally favorable state toward accepting inducers by increasing the accessibility to the ligand-binding pocket. Hence, it can be concluded that conformational changes are facilitated through a pendulum-like rearrangement of the fluid dimeric interface (Figure 8). Each monomer rotates along the dimeric axis with the direction of rotation being determined so as to facilitate operator binding. These kinds of allosteric transitions that facilitate function are seen in various transcription factors that are regulated by small molecule inducers (25,60). For example, the well-established system, LacR, similar to TetR-FTRs, also adopts different conformations in the DNA, and the small molecule repressor (IPTG) bound forms; a subtle switch between these states controls its transcriptional activity (61). In contrast, there are also systems like the tetrameric gene regulator, TtgV, a multidrug-binding protein and controller of efflux pump, which undergo drastic conformational changes (like the wings of a flying bird) in structure between its operator and inducer-bound forms to assist function (62).

Bottom Line: Binding of the DNA results in the restructuring of the dimeric interface of CprB, inducing a pendulum-like motion of the helix-turn-helix motif that inserts into the major groove.Experiments performed on a subset of DNA sequences from Streptomyces coelicolor A3(2) suggest that CprB is most likely a pleiotropic regulator.Apart from serving as an autoregulator, it is potentially a part of a network of proteins that modulates the γ-butyrolactone synthesis and antibiotic regulation pathways in S. coelicolor A3(2).

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, Maharashtra, India IITB-Monash Research Academy, Mumbai 400076, Maharashtra, India.

Show MeSH
Related in: MedlinePlus