ArticleThe Journal of biological chemistry2014
Redox regulation of methionine aminopeptidase 2 activity.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Determining the Redox Potential of a Protein Disulfide Bond.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Classification of Protein Disulfide Bonds.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Destined for destruction: The role of methionine aminopeptidases and plant cysteine oxidases in N-degron formation.Plant physiology · 2024Review
- Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models.Molecular cancer therapeutics · 2024Article
- Impact of Protein NLife (Basel, Switzerland) · 2023Review
- The Potential Role of the Methionine Aminopeptidase GeneInternational journal of molecular sciences · 2022Article
- Methionine aminopeptidase 2 as a potential target in pancreatic ductal adenocarcinoma.American journal of translational research · 2022Article
- MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease.Blood advances · 2021Article
- Redox Potentials of Disulfide Bonds in LOXL2 Studied by Nonequilibrium Alchemical Simulation.Frontiers in chemistry · 2021Article
- Allosteric disulphide bonds as reversible mechano-sensitive switches that control protein functions in the vasculature.Biophysical reviews · 2019Review
- Allosteric disulfides: Sophisticated molecular structures enabling flexible protein regulation.The Journal of biological chemistry · 2019Review
- Mechano-redox control of integrin de-adhesion.eLife · 2018Article
- Identification of allosteric disulfides from labile bonds in X-ray structures.Royal Society open science · 2018Article
- Autoregulation of von Willebrand factor function by a disulfide bond switch.Science advances · 2018Article
- Group VII Ethylene Response Factors in Arabidopsis: Regulation and Physiological Roles.Plant physiology · 2018Review
- Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein translation is initiated with methionine in eukaryotes, and the majority of proteins have their N-terminal methionine removed by methionine aminopeptidases (MetAP1 and MetAP2) prior to action. Methionine removal can be important for protein function, localization, or stability. No mechanism of regulation of MetAP activity has been identified. MetAP2, but not MetAP1, contains a single Cys(228)-Cys(448) disulfide bond that has an -RHStaple configuration and links two β-loop structures, which are hallmarks of allosteric disulfide bonds. From analysis of crystal structures and using mass spectrometry and activity assays, we found that the disulfide bond exists in oxidized and reduced states in the recombinant enzyme. The disulfide has a standard redox potential of -261 mV and is efficiently reduced by the protein reductant, thioredoxin, with a rate constant of 16,180 m(-1) s(-1). The MetAP2 disulfide bond also exists in oxidized and reduced states in glioblastoma tumor cells, and stressing the cells by oxygen or glucose deprivation results in more oxidized enzyme. The Cys(228)-Cys(448) disulfide is at the rim of the active site and is only three residues distant from the catalytic His(231), which suggested that cleavage of the bond would influence substrate hydrolysis. Indeed, oxidized and reduced isoforms have different catalytic efficiencies for hydrolysis of MetAP2 peptide substrates. These findings indicate that MetAP2 is post-translationally regulated by an allosteric disulfide bond, which controls substrate specificity and catalytic efficiency.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.