Mycobacterial stress regulation: The Dps “twin sister” defense mechanism and structure‐function relationship

Chowdhury, Rebecca; Saraswathi, R.; Chatterji, Dipankar

doi:10.1002/iub.285

Cited by 18 publications

(20 citation statements)

References 64 publications

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“…Furthermore, changes in colony morphology within a given species of Mycobacterium can have differential effects on the signaling events initiated in infected cells, resulting in a degree of difference in virulence as well as in mycobacterial survival (65)(66)(67). For example, among an isogenic pair of Mycobacterium avium morphotypes, whereas the virulent smooth transparent (SmT) morphotype proliferated in murine macrophages in a p38 mitogen-activated protein kinase activation-dependent manner, proliferation of the less virulent smooth opaque (SmO) morphotype to some extent was dependent upon ERK1/2 activation (68,69).…”

Section: Pe_pgrs11-induced Resistance To Oxidative Stress Necessitatementioning

confidence: 99%

The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress

Chaturvedi

Bansal

Narayana

et al. 2010

Journal of Biological Chemistry

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Mycobacterium tuberculosis utilizes unique strategies to survive amid the hostile environment of infected host cells. Infection-specific expression of a unique mycobacterial cell surface antigen that could modulate key signaling cascades can act as a key survival strategy in curtailing host effector responses like oxidative stress. We demonstrate here that hypothetical PE_PGRS11 ORF encodes a functional phosphoglycerate mutase. The transcriptional analysis revealed that PE_PGRS11 is a hypoxia-responsive gene, and enforced expression of PE_PGRS11 by recombinant adenovirus or Mycobacterium smegmatis imparted resistance to alveolar epithelial cells against oxidative stress. PE_PGRS11-induced resistance to oxidative stress necessitated the modulation of genetic signatures like induced expression of Bcl2 or COX-2. This modulation of specific antiapoptotic molecular signatures involved recognition of PE_PGRS11 by TLR2 and subsequent activation of the PI3K-ERK1/2-NF-B signaling axis. Furthermore, PE_PGRS11 markedly diminished H 2 O 2 -induced p38 MAPK activation. Interestingly, PE_PGRS11 protein was exposed at the mycobacterial cell surface and was involved in survival of mycobacteria under oxidative stress. Furthermore, PE_PGRS11 displayed differential B cell responses during tuberculosis infection. Taken together, our investigation identified PE_PGRS11 as an in vivo expressed immunodominant antigen that plays a crucial role in modulating cellular life span restrictions imposed during oxidative stress by triggering TLR2-dependent expression of COX-2 and Bcl2. These observations clearly provide a mechanistic basis for the rescue of pathogenic Mycobacterium-infected lung epithelial cells from oxidative stress.

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Section: Pe_pgrs11-induced Resistance To Oxidative Stress Necessitatementioning

confidence: 99%

The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress

Chaturvedi

Bansal

Narayana

et al. 2010

Journal of Biological Chemistry

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“…Furthermore, gene expression of various ferritins appears to be differentially regulated and modulated by many environmental factors [25]. Literature on ferritins corroborates the importance of these proteins for the adaptive response of the organism to environmental changes [26], [27], [28] and the coexistence of multiple ferritin paralogues within an organism is indicative of the fact that they fulfill disparate physiological roles.…”

Section: Introductionmentioning

confidence: 81%

Ferritin Structure from Mycobacterium tuberculosis: Comparative Study with Homologues Identifies Extended C-Terminus Involved in Ferroxidase Activity

et al. 2011

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Ferritins are recognized as key players in the iron storage and detoxification processes. Iron acquisition in the case of pathogenic bacteria has long been established as an important virulence mechanism. Here, we report a 3.0 Å crystal structure of a ferritin, annotated as Bacterioferritin B (BfrB), from Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis that continues to be one of the world's deadliest diseases. Similar to the other members of ferritin family, the Mtb BfrB subunit exhibits the characteristic fold of a four-helical bundle that possesses the ferroxidase catalytic centre. We compare the structure of Mtb BfrB with representatives of the ferritin family belonging to the archaea, eubacteria and eukarya. Unlike most other ferritins, Mtb BfrB has an extended C-terminus. To dissect the role of this extended C-terminus, truncated Mtb BfrB was purified and biochemical studies implicate this region in ferroxidase activity and iron release in addition to providing stability to the protein. Functionally important regions in a protein of known 3D-structure can be determined by estimating the degree of conservation of the amino-acid sites with its close homologues. Based on the comparative studies, we identify the slowly evolving conserved sites as well as the rapidly evolving variable sites and analyze their role in relation to structure and function of Mtb BfrB. Further, electrostatic computations demonstrate that although the electrostatic environment of catalytic residues is preserved within the family, extensive variability is exhibited by residues defining the channels and pores, in all likelihood keeping up with the diverse functions executed by these ferritins in varied environments.

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“…28,29 For example Deinococcus radiodurans Dps-1 was reported to switch from a 12-mer to a dimer upon buffer exchange from high to low salt 30 and the Listeria innocua DPS 12-mer can be made to dissociate to a dimer by lowering the pH below 2.0. 31 Moreover, Dps from Mycobacterium smegmatis dissociates into lower order oligomers at low temperature (4 C).…”

Section: Discussionmentioning

confidence: 99%

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

Zhang

Chee

et al. 2011

Protein Science

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DNA-binding protein from starved cells (DPS), a mini-ferritin capable of self-assembling into a 12-meric nano-cage, was chosen as the basis for an alanine-shaving mutagenesis study to investigate the importance of key amino acid residues, located at symmetry-related protein-protein interfaces, in controlling protein stability and self-assembly. Nine mutants were designed through simple inspection, synthesized, and subjected to transmission electron microscopy, circular dichroism, size exclusion chromatography, and ''virtual alanine scanning'' computational analysis. The data indicate that many of these residues may be hot spot residues. Most remarkably, two residues, R83 and R133, were observed to shift the oligomerization state to~50% dimer. Based on the hypothesis that these two residues constitute a ''hot strip,'' located at the ferritin-like threefold axis, the double mutant was generated which completely shuts down detectable formation of 12-mer in solution, favoring a cooperatively folded dimer. The fact that this effect logically builds upon the single mutants emphasizes that complex self-assembly has the potential to be manipulated rationally. This study should have an impact on the fundamental understanding of the assembly of DPS protein cages specifically and protein quaternary structure in general. In addition, as there is much interest in applying these and similar systems to the templation of nano-materials and drug delivery, the ability to control this ferritin's oligomerization state and stability could prove especially valuable.

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Mycobacterial stress regulation: The Dps “twin sister” defense mechanism and structure‐function relationship

Cited by 18 publications

References 64 publications

The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress

The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress

Ferritin Structure from Mycobacterium tuberculosis: Comparative Study with Homologues Identifies Extended C-Terminus Involved in Ferroxidase Activity

Rational disruption of the oligomerization of the mini‐ferritin E. coli DPS through protein‐protein interface mutation

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