Lipid modification of the Cu,Zn superoxide dismutase from Mycobacterium tuberculosis

D’Orazio, Melania; Folcarelli, Silvia; Mariani, Francesca; Colizzi, Vittorio; Rotilio, Giuseppe; Battistoni, Andrea

doi:10.1042/0264-6021:3590017

Cited by 29 publications

(23 citation statements)

References 41 publications

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“…53 This MtSOD is up-regulated and expressed on the extracellular surface of the mycobacterium upon entry into human macrophages, where superoxide levels are expected to be high. 54 Despite the absence of zinc, MtSOD has an enzymatic rate comparable to that of most Cu,Zn SODs. 53 Consistent with zinc-deficient human SOD, the rate of superoxide dismutation of M. tuberculosis is pH dependent.…”

Section: Discussionmentioning

confidence: 99%

Structural Characterization of Zinc-deficient Human Superoxide Dismutase and Implications for ALS

Roberts

Tainer

Getzoff

et al. 2007

Journal of Molecular Biology

134

123

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Over 130 mutations to copper, zinc superoxide dismutase (SOD) are implicated in the selective death of motor neurons found in 25% of patients with familial amyotrophic lateral sclerosis (ALS). Despite their widespread distribution, ALS mutations appear positioned to cause structural and misfolding defects. Such defects decrease SOD's affinity for zinc, and loss of zinc from SOD is sufficient to induce apoptosis in motor neurons in vitro. To examine the importance of the zinc site in the structure and pathogenesis of human SOD, we determined the 2.0-A-resolution crystal structure of a designed zinc-deficient human SOD, in which two zinc-binding ligands have been mutated to hydrogen-bonding serine residues. This structure revealed a 9 degrees twist of the subunits, which opens the SOD dimer interface and represents the largest intersubunit rotational shift observed for a human SOD variant. Furthermore, the electrostatic loop and zinc-binding subloop were partly disordered, the catalytically important Arg143 was rotated away from the active site, and the normally rigid intramolecular Cys57-Cys146 disulfide bridge assumed two conformations. Together, these changes allow small molecules greater access to the catalytic copper, consistent with the observed increased redox activity of zinc-deficient SOD. Moreover, the dimer interface is weakened and the Cys57-Cys146 disulfide is more labile, as demonstrated by the increased aggregation of zinc-deficient SOD in the presence of a thiol reductant. However, equimolar Cu,Zn SOD rapidly forms heterodimers with zinc-deficient SOD (t1/2 approximately 15 min) and prevents aggregation. The stabilization of zinc-deficient SOD as a heterodimer with Cu,Zn SOD may contribute to the dominant inheritance of ALS mutations. These results have general implications for the importance of framework stability on normal metalloenzyme function and specific implications for the role of zinc ion in the fatal neuropathology associated with SOD mutations.

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Section: Discussionmentioning

confidence: 99%

Structural Characterization of Zinc-deficient Human Superoxide Dismutase and Implications for ALS

Roberts

Tainer

Getzoff

et al. 2007

Journal of Molecular Biology

134

123

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“…The pellet was resuspended in 10 mmol/L Tris-HCl, 1 mmol/L EDTA, and 150 mmol/L NaCl; incubated for 24 h with 10 mg/mL lysozyme; and then lysed by 3 sonication cycles for 60 s at 20 KHz under cooling with ice water. Sonicated cells were centrifuged at 25,000 g for 15 min at 4ЊC, and the supernatant, including membranes and cytosolic proteins, was subjected to Triton X-114 partitioning, as described elsewhere [22]. The 19-kDa lipoprotein antigen was then purified from SDS-discontinuous polyacrylamide gels prepared according to standard procedures [23].…”

Section: Methodsmentioning

confidence: 99%

Induction of Apoptosis and Release of Interleukin‐1β by Cell Wall–Associated 19‐kDa Lipoprotein during the Course of Mycobacterial Infection

et al. 2004

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Mycobacterium tuberculosis induces apoptosis in human monocyte-derived macrophages (MDMs) during the early stages of infection. We investigated the proapoptotic role of cell wall-associated mycobacterial 19-kDa lipoprotein and the possible association between 19-kDa lipoprotein signaling and production of proinflammatory cytokines. Purified mycobacterial 19-kDa lipoprotein, 19-kDa lipoprotein-expressing M. smegmatis (M. smegmatis 19+), 19-kDa lipoprotein knockout (KO) M. tuberculosis, and 19-kDa lipoprotein KO M. bovis bacille Calmette-Guerin (BCG) strains were analyzed for their ability to induce apoptosis in MDMs. The 19-kDa lipoprotein and infection with M. smegmatis 19+ induced apoptosis in MDMs. M. tuberculosis and BCG KO strains had significantly decreased abilities to induce apoptosis. The 19-kDa lipoprotein proapoptotic signal was mediated by Toll-like receptor 2 but not by tumor necrosis factor-alpha. Only the release of interleukin (IL)-1 beta was decreased after infection with 19-kDa lipoprotein KO strains. These findings indicate that the 19-kDa lipoprotein is the main signal required to trigger both apoptosis and the release of IL-1 beta during the early stages of mycobacterial infection.

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“…The function of Sod enzymes is the detoxification of ROS by conversion of O 2 - into molecular oxygen and hydrogen peroxide 226 . SodC is a copper-containing SOD outer-membrane lipoprotein 227 , 228 involved in the protection of M. tuberculosis against the extracellular superoxide generated by host cells. Consistently, sodC transcription is upregulated upon macrophage infection 229 .…”

Section: Proteins Inhibiting Antimicrobial Responses Of the Macrophagementioning

confidence: 99%

Virulence factors of theMycobacterium tuberculosiscomplex

et al. 2013

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The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world.

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Lipid modification of the Cu,Zn superoxide dismutase from Mycobacterium tuberculosis

Cited by 29 publications

References 41 publications

Structural Characterization of Zinc-deficient Human Superoxide Dismutase and Implications for ALS

Structural Characterization of Zinc-deficient Human Superoxide Dismutase and Implications for ALS

Induction of Apoptosis and Release of Interleukin‐1β by Cell Wall–Associated 19‐kDa Lipoprotein during the Course of Mycobacterial Infection

Virulence factors of theMycobacterium tuberculosiscomplex

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