ArticleThe Journal of biological chemistry2015
Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export.bioRxiv : the preprint server for biology · 2026Article
- A structural bioinformatics framework for prioritizing pH-sensitive proteins from 3D structural features.BMC bioinformatics · 2026Article
- Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors.Nature communications · 2025Article
- Molecular and functional profiling of Gαi as an intracellular pH sensor.Nature communications · 2025Article
- How Electricity Prevents Us from Bleeding to Death.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Evolution of pH-sensitive transcription termination inProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Prodomain-driven enzyme dimerization: a pH-dependent autoinhibition mechanism that controlsmBio · 2024Article
- Evolution of pH-sensitive transcription termination during adaptation to repeated long-term starvation.bioRxiv : the preprint server for biology · 2024Article
- Expression profiles of respiratory V-ATPase and calprotectin in SARS-CoV-2 infection.Cell death discovery · 2022Article
- Novel Homozygous Inactivating Mutation in theGenes · 2021Article
- Does Covera-19 know 'when to hold 'em or 'when to fold 'em? A translational thought experiment.Translational medicine communications · 2021Review
- Systematic Comparison of Vesicular Targeting Signals Leads to the Development of Genetically Encoded Vesicular Fluorescent ZnACS sensors · 2020Article
- Characterization of differential pore-forming activities of ESAT-6 proteins from Mycobacterium tuberculosis and Mycobacterium smegmatis.FEBS letters · 2016Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The propeptides of proprotein convertases (PCs) regulate activation of cognate protease domains by sensing pH of their organellar compartments as they transit the secretory pathway. Earlier experimental work identified a conserved histidine-encoded pH sensor within the propeptide of the canonical PC, furin. To date, whether protonation of this conserved histidine is solely responsible for PC activation has remained unclear because of the observation that various PC paralogues are activated at different organellar pH values. To ascertain additional determinants of PC activation, we analyzed PC1/3, a paralogue of furin that is activated at a pH of ∼5.4. Using biophysical, biochemical, and cell-based methods, we mimicked the protonation status of various histidines within the propeptide of PC1/3 and examined how such alterations can modulate pH-dependent protease activation. Our results indicate that whereas the conserved histidine plays a crucial role in pH sensing and activation of this protease an additional histidine acts as a "gatekeeper" that fine-tunes the sensitivity of the PC1/3 propeptide to facilitate the release inhibition at higher proton concentrations when compared with furin. Coupled with earlier analyses that highlighted the enrichment of the amino acid histidine within propeptides of secreted eukaryotic proteases, our work elucidates how secreted proteases have evolved to exploit the pH of the secretory pathway by altering the spatial juxtaposition of titratable groups to regulate their activity in a spatiotemporal fashion.
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