Dataset Information

Structural Insights into a Bifunctional Peptide Methionine Sulfoxide Reductase MsrA/B Fusion Protein from Helicobacter pylori.

ABSTRACT: Methionine sulfoxide reductase (Msr) is a family of enzymes that reduces oxidized methionine and plays an important role in the survival of bacteria under oxidative stress conditions. MsrA and MsrB exist in a fusion protein form (MsrAB) in some pathogenic bacteria, such as Helicobacter pylori (Hp), Streptococcus pneumoniae, and Treponema denticola. To understand the fused form instead of the separated enzyme at the molecular level, we determined the crystal structure of HpMsrABC44S/C318S at 2.2 Å, which showed that a linker region (Hpiloop, 193-205) between two domains interacted with each HpMsrA or HpMsrB domain via three salt bridges (E193-K107, D197-R103, and K200-D339). Two acetate molecules in the active site pocket showed an sp2 planar electron density map in the crystal structure, which interacted with the conserved residues in fusion MsrABs from the pathogen. Biochemical and kinetic analyses revealed that Hpiloop is required to increase the catalytic efficiency of HpMsrAB. Two salt bridge mutants (D193A and E199A) were located at the entrance or tailgate of Hpiloop. Therefore, the linker region of the MsrAB fusion enzyme plays a key role in the structural stability and catalytic efficiency and provides a better understanding of why MsrAB exists in a fused form.

SUBMITTER: Kim S

PROVIDER: S-EPMC8000184 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Structural Insights into a Bifunctional Peptide Methionine Sulfoxide Reductase MsrA/B Fusion Protein from Helicobacter pylori.

Kim Sulhee S Lee Kitaik K Park Sun-Ha SH Kwak Geun-Hee GH Kim Min Seok MS Kim Hwa-Young HY Hwang Kwang Yeon KY

Antioxidants (Basel, Switzerland) 20210305 3

Methionine sulfoxide reductase (Msr) is a family of enzymes that reduces oxidized methionine and plays an important role in the survival of bacteria under oxidative stress conditions. MsrA and MsrB exist in a fusion protein form (MsrAB) in some pathogenic bacteria, such as Helicobacter pylori (Hp), Streptococcus pneumoniae, and Treponema denticola. To understand the fused form instead of the separated enzyme at the molecular level, we determined the crystal structure ...[more]

PMID: 33807684

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Project description:Methionine restriction (MR) extends lifespan in various model organisms, and understanding the molecular effectors of MR could expand the repertoire of tools targeting the aging process. Here, we address to what extent the biochemical pathway responsible for redox metabolism of methionine plays in regulating the effects of MR on lifespan and health span. Aerobic organisms have evolved methionine sulfoxide reductases to counter the oxidation of the thioether group contained in the essential amino acid methionine. Of these enzymes, methionine sulfoxide reductase A (MsrA) is ubiquitously expressed in mammalian tissues and has subcellular localization in both the cytosol and mitochondria. Loss of MsrA increases sensitivity to oxidative stress and has been associated with increased susceptibility to age-associated pathologies including metabolic dysfunction. We rationalized that limiting the available methionine with MR may place increased importance on methionine redox pathways, and that MsrA may be required to maintain available methionine for its critical uses in cellular homeostasis including protein synthesis, metabolism, and methylation. Using a genetic mutant mouse lacking MsrA, we tested the requirement for this enzyme in the effects of MR on longevity and markers of healthy aging late in life. When initiated in adulthood, we found that MR had minimal effects in males and females regardless of MsrA status. MR had minimal effect on lifespan with the exception of wild-type males where loss of MsrA slightly increased lifespan on MR. We also observed that MR drove an increase in body weight in wild-type mice only, but mice lacking MsrA tended to maintain more stable body weight throughout their lives. We also found that MR had greater benefit to males than females in terms of glucose metabolism and some functional health span assessments, but MsrA generally had minimal impact on these metrics. Frailty was also found to be unaffected by MR or MsrA in aged animals. We found that in general, MsrA was not required for the beneficial effects of MR on longevity and health span.

Dataset Information

Structural Insights into a Bifunctional Peptide Methionine Sulfoxide Reductase MsrA/B Fusion Protein from Helicobacter pylori.

Publications

Structural Insights into a Bifunctional Peptide Methionine Sulfoxide Reductase MsrA/B Fusion Protein from <i>Helicobacter pylori</i>.

Similar Datasets

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