ArticleThe Journal of biological chemistry2013
The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Trial
- A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export.bioRxiv : the preprint server for biology · 2026Article
- Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors.Nature communications · 2025Article
- Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.Nature microbiology · 2024Article
- Prodomain-driven enzyme dimerization: a pH-dependent autoinhibition mechanism that controlsmBio · 2024Article
- Novel Homozygous Inactivating Mutation in theGenes · 2021Article
- SARS-CoV-2 and other human coronaviruses: Mapping of protease recognition sites, antigenic variation of spike protein and their grouping through molecular phylogenetics.Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases · 2021Article
- Molecular evolution of PCSK family: Analysis of natural selection rate and gene loss.PloS one · 2021Article
- Does Covera-19 know 'when to hold 'em or 'when to fold 'em? A translational thought experiment.Translational medicine communications · 2021Review
- Specific and Selective Inhibitors of Proprotein Convertases Engineered by Transferring Serpin B8 Reactive-Site and Exosite Determinants of Reactivity to the Serpin α1PDX.Biochemistry · 2019Article
- Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases.Scientific reports · 2018Article
- pH-regulated metal-ligand switching in the HM loop of ATP7A: a new paradigm for metal transfer chemistry.Metallomics : integrated biometal science · 2016Article
- Cysteine Proteases: Modes of Activation and Future Prospects as Pharmacological Targets.Frontiers in pharmacology · 2016Review
- Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3.The Journal of biological chemistry · 2015Article
- Determination of Histidine pKa Values in the Propeptides of Furin and Proprotein Convertase 1/3 Using Histidine Hydrogen-Deuterium Exchange Mass Spectrometry.Analytical chemistry · 2015Article
- Acidic pH and divalent cation sensing by PhoQ are dispensable for systemic salmonellae virulence.eLife · 2015Article
- Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis.Virus research · 2015Review
- Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- A histidine-rich linker region in peptidylglycine α-amidating monooxygenase has the properties of a pH sensor.The Journal of biological chemistry · 2014Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 → Leu mutant that blocks furin activation in vivo revealed protonation of His-69 reduces both the thermodynamic stability of the propeptide as well as its affinity for furin at pH 6.0. Structural modeling combined with mathematical modeling and molecular dynamic simulations suggested that His-69 does not directly contribute to the propeptide-enzyme interface but, rather, triggers movement of a loop region in the propeptide that modulates access to the cleavage site and, thus, allows for the tight pH regulation of furin activation. Our work establishes a mechanism by which His-69 functions as a pH sensor that regulates compartment-specific furin activation and provides insights into how other convertases and proteases may regulate their precise spatiotemporal activation.
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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.