Membranous adenylyl cyclase 1 activation is regulated by oxidation of N- and C-terminal methionine residues in calmodulin

Lübker, Carolin; Urbauer, Ramona J. Bieber; Moskovitz, Jackob; Dove, Stefan; Weisemann, Jasmin; Fedorova, Maria; Urbauer, Jeffrey L.; Seifert, Roland

doi:10.1016/j.bcp.2014.11.007

Cited by 10 publications

(22 citation statements)

References 73 publications

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“…These results suggest that only the affinity of EF and CaM is affected by the degree of Met oxidation using 5 mM H 2 O 2 , but the maximal CaM stimulation of EF is only affected by completely oxidized CaM with 50 mM H 2 O 2 . In fact, CaM oxidized with 5 mM or 50 mM H 2 O 2 showed similar degrees of Met oxidation analyzed by SDS-PAGE in a previous study of our group [ 19 ], but the above observations confirm the hypothesis that SDS-PAGE is not a suitable method for analyzing subtle differences in the degree of Met oxidation of CaM [ 19 ].…”

Section: Resultssupporting

confidence: 81%

“…EF was fully activated by CaM-wt oxidized with 5 mM H 2 O 2 with only a moderate decrease in potency. However, with completely oxidized CaM-wt (50 mM H 2 O 2 ) with all nine Met residues oxidized to MetSO (as shown by previous mass spectrometry analysis [ 19 , 23 ]), no EF activation was observed ( Table 2 ). In contrast, EF activation was not affected by oxidized CaM-mut, which contains up to three MetSO ( Table 2 ).…”

Section: Discussionsupporting

confidence: 55%

“…It remains to be determined how Mn 2+ (used instead of Mg 2+ in the present study) affects EF regulation by CaM. Based on these results, a concentration of 10 μM free Ca 2+ , analogously to experiments analyzing AC1 activation [ 19 ], was used for subsequent studies analyzing CaM stimulation of EF.…”

Section: Resultsmentioning

confidence: 99%

“…The data also indicate that binding of CaM to EF is affected by the secondary structure of CaM, which is suggested to be associated with Met oxidation. We have shown that the α-helical content of CaM-wt and L2-CaM decreases only moderately, but significantly, upon oxidation [ 19 ]. It is reasonable that the reduction of the α-helical content, especially in the N-terminal region due to oxidation of the N -terminal Met residues (M36, M51, M71, M72 and M76), is critical for binding of CaM to EF.…”

Section: Discussionmentioning

confidence: 99%

“…All these data prompted us to study activation of EF by in vitro oxidized CaM. In order to analyze the impact of the redox state of distinct Met on EF activation, we used 13 CaM-mutants (CaM-mut) with site-specific Met to leucine (Leu) substitutions ( Table 1 ), which were previously analyzed with regard to activation of mammalian membranous adenylyl cyclase 1 (AC1) [ 19 ]. Leu is comparable to Met in terms of hydrophobicity, volume, and the preference for forming α-helices [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor

Lübker

Dove

Tang

et al. 2015

Toxins

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Bacillus anthracis adenylyl cyclase toxin edema factor (EF) is one component of the anthrax toxin and is essential for establishing anthrax disease. EF activation by the eukaryotic Ca2+-sensor calmodulin (CaM) leads to massive cAMP production resulting in edema. cAMP also inhibits the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, thus reducing production of reactive oxygen species (ROS) used for host defense in activated neutrophils and thereby facilitating bacterial growth. Methionine (Met) residues in CaM, important for interactions between CaM and its binding partners, can be oxidized by ROS. We investigated the impact of site-specific oxidation of Met in CaM on EF activation using thirteen CaM-mutants (CaM-mut) with Met to leucine (Leu) substitutions. EF activation shows high resistance to oxidative modifications in CaM. An intact structure in the C-terminal region of oxidized CaM is sufficient for major EF activation despite altered secondary structure in the N-terminal region associated with Met oxidation. The secondary structures of CaM-mut were determined and described in previous studies from our group. Thus, excess cAMP production and the associated impairment of host defence may be afforded even under oxidative conditions in activated neutrophils.

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Section: Resultssupporting

confidence: 81%

Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor

Lübker

Dove

Tang

et al. 2015

Toxins

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Regulation of cardiac fibrosis in mice with TAC/DOCA‐induced HFpEF by resistin‐like molecule gamma and adenylate cyclase 1

Liu,

Zeng,

Chen

et al. 2024

FEBS Open Bio

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Heart failure with preserved ejection fraction (HFpEF) is one of the major subtypes of heart failure (HF) and no effective treatments for this common disease exist to date. Cardiac fibrosis is central to the pathology of HF and a potential avenue for the treatment of HFpEF. To explore key fibrosis‐related genes and pathways in the pathophysiological process of HFpEF, a mouse model of HFpEF was constructed. The relevant gene expression profiles were downloaded from the Gene Expression Omnibus database, and single‐sample Gene Set Enrichment Analysis (ssGSEA) was performed targeting fibrosis‐related pathways to explore differentially expressed genes (DEGs) in healthy control and HFpEF heart tissues with cross‐tabulation analysis of fibrosis‐related genes. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the identified fibrosis‐related genes. The two most significant DEGs were selected, and further validation was conducted in HFpEF mice. The results indicated that myocardial fibrosis was significantly upregulated in HFpEF mice compared to healthy controls, while the ssGSEA results revealed significant differences in the enrichment of nine fibrosis‐related pathways in HFpEF myocardial tissue, with 112 out of 798 DEGs being related to fibrosis. The in vivo results demonstrated that expression levels of resistin‐like molecule gamma (Relmg) and adenylate cyclase 1 (Adcy1) in the heart tissues of HFpEF mice were significantly higher and lower, respectively, compared to healthy controls. Taken together, these results suggest that Relmg and Acdy1 as well as the fibrosis process may be potential targets for HFpEF treatment.

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CUX2 prevents the malignant progression of gliomas by enhancing ADCY1 transcription

Yao¹,

Le²,

Min

et al. 2022

Exp Brain Res

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Membranous adenylyl cyclase 1 activation is regulated by oxidation of N- and C-terminal methionine residues in calmodulin

Cited by 10 publications

References 73 publications

Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor

Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor

Regulation of cardiac fibrosis in mice with TAC/DOCA‐induced HFpEF by resistin‐like molecule gamma and adenylate cyclase 1

CUX2 prevents the malignant progression of gliomas by enhancing ADCY1 transcription

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