Molecular determinants of human dipeptidyl peptidase III sensitivity to thiol modifying reagents

Karačić, Zrinka; Špoljarić, Jasminka; Rožman, Marko; Abramić, Marija

doi:10.1515/hsz-2012-0181

Cited by 9 publications

(6 citation statements)

References 24 publications

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“…A significant drop in GSSG and restoration of cytosolic DPP III protein content was achieved by subsequent administration of E 2 . The inverse relationship between GSSG and Dpp III level found in this study emphasizes previous finding which showed that GSSG is an inactivator of DPP III [33] . Oxidation of cysteine residues might also have an effect on lowering enzymatic activity of DPP III that has remained the same in all groups despite the higher amounts of the protein in hovxe group compared to hovx, and to a lesser extent between hsham and sham group.…”

Section: Discussionsupporting

confidence: 89%

Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo

et al. 2016

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A number of age-related diseases have a low incidence in females, which is attributed to a protective effect of sex hormones. For instance, the female sex hormone estrogen (E2) has a well established cytoprotective effect against oxidative stress, which strongly contributes to ageing. However, the mechanism by which E2 exerts its protective activity remains elusive.In this study we address the question whether the E2-induced protective effect against hyperoxia is mediated by the Nrf-2/Keap-1 signaling pathway. In particular, we investigate the E2-induced expression and cellular distribution of DPP III monozinc exopeptidase, a member of the Nrf-2/Keap-1 pathway, upon hyperoxia treatment.We find that DPP III accumulates in the nucleus in response to hyperoxia. Further, we show that combined induction of hyperoxia and E2 administration have an additive effect on the nuclear accumulation of DPP III. The level of nuclear accumulation of DPP III is comparable to nuclear accumulation of Nrf-2 in healthy female mice exposed to hyperoxia. In ovariectomized females exposed to hyperoxia, supplementation of E2 induced upregulation of DPP III, Ho-1, Sirt-1 and downregulation of Ppar-γ. While other cytoprotective mechanisms cannot be excluded, these findings demonstrate a prominent role of DPP III, along with Sirt-1, in the E2-mediated protection against hyperoxia.

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Section: Discussionsupporting

confidence: 89%

Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo

et al. 2016

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“…Even before the crystal structure of human DPP III ligand complex was resolved, our observation that Cys176, a residue from the lower domain, quite distant from the active centre (44 Å apart from the catalytic zinc ion in the crystal structure of ligand-free human DPP III), is responsible for the fast inactivation by the organomercurial compound, provided the evidence that the active site of human DPP III comprises both protein domains, which in the active form of the enzyme need to be in close contact [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of dipeptidyl peptidase III from the human gut symbiont Bacteroides thetaiotaomicron

et al. 2017

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Bacteroides thetaiotaomicron is a dominant member of the human intestinal microbiome. The genome of this anaerobe encodes more than 100 proteolytic enzymes, the majority of which have not been characterized. In the present study, we have produced and purified recombinant dipeptidyl peptidase III (DPP III) from B. thetaiotaomicron for the purposes of biochemical and structural investigations. DPP III is a cytosolic zinc-metallopeptidase of the M49 family, involved in protein metabolism. The biochemical results for B. thetaiotaomicron DPP III from our research showed both some similarities to, as well as certain differences from, previously characterised yeast and human DPP III. The 3D-structure of B. thetaiotaomicron DPP III was determined by X-ray crystallography and revealed a two-domain protein. The ligand-free structure (refined to 2.4 Å) was in the open conformation, while in the presence of the hydroxamate inhibitor Tyr-Phe-NHOH, the closed form (refined to 3.3 Å) was observed. Compared to the closed form, the two domains of the open form are rotated away from each other by about 28 degrees. A comparison of the crystal structure of B. thetaiotaomicron DPP III with that of the human and yeast enzymes revealed a similar overall fold. However, a significant difference with functional implications was discovered in the upper domain, farther away from the catalytic centre. In addition, our data indicate that large protein flexibility might be conserved in the M49 family.

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“…However, we still do not know how CAT2 affects LAP2 activity. Previous reports showed that the peptidase activity of human dipeptidyl peptidase 8 and 9 was severely inhibited following H 2 O 2 treatment, and moreover, reducing agents completely reversed this oxidation-mediated enzyme activity abrogation ( Park et al, 2008 ); in addition, human dipeptidyl peptidase III could be inactivated by oxidized glutathione (GSSH), and the oxidation of the cysteine 176 participated in this enzyme inhibition ( Karacic et al, 2012 ). These reports revealed that peptidases may be ROS-sensitive enzymes and their hydrolysis activity requires a reducing environment.…”

Section: Discussionmentioning

confidence: 99%

Mutual Promotion of LAP2 and CAT2 Synergistically Regulates Plant Salt and Osmotic Stress Tolerance

Zhang

Wang

Li³

et al. 2021

Front. Plant Sci.

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Almost all abiotic stresses induce reactive oxygen species (ROS) overaccumulation, causing oxidative damages to plant cells. Catalase (CAT) plays a vital role in plant oxidative stress tolerance by scavenging stress-induced excess H2O2; thus, the identification of factors regulating catalase function will shed light on the underlying regulatory mechanisms. Here, we identified leucine aminopeptidase 2 (LAP2) as a novel CAT2-interacting protein and showed a mutual promotion effect of the two proteins in plant stress responses. LAP2 has a physical interaction with CAT2 in plant cells. The loss-of-function mutant of LAP2, lap2-3, is hypersensitive to salt or osmotic stress with increased ROS accumulation and malondialdehyde content and decreased catalase activity. The lap2-3 mutant has less CAT2 protein levels as CAT2 protein stability is impaired in the mutant. Scavenging excess ROS by glutathione or overexpressing CAT2 in the lap2-3 mutant recovers its hypersensitive phenotype to salt or osmotic stress. Further study showed that CAT2 promotes LAP2 hydrolysis activity with leucine-4-methylcoumaryl-7-amides as a substrate in vivo and in vitro, and thus, similar to the lap2-3 mutant, the cat2-1 mutant also has lower γ-aminobutyric acid content than the wild type. Together, our study reveals mutual promotion effects of CAT2 and LAP2 in conferring plant salt and osmotic stress tolerance.

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Molecular determinants of human dipeptidyl peptidase III sensitivity to thiol modifying reagents

Cited by 9 publications

References 24 publications

Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo

Prominent role of exopeptidase DPP III in estrogen-mediated protection against hyperoxia in vivo

Crystal structure of dipeptidyl peptidase III from the human gut symbiont Bacteroides thetaiotaomicron

Mutual Promotion of LAP2 and CAT2 Synergistically Regulates Plant Salt and Osmotic Stress Tolerance

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