ArticleThe Journal of biological chemistry2006
Identification of a pH sensor in the furin propeptide that regulates enzyme activation.
Article in The Journal of biological chemistry, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Pooled it
- Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors.Nature communications · 2025Article
- Monensin suppresses EMT-driven cancer cell motility by inducing Golgi pH-dependent exocytosis of GOLIM4.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype inOpen biology · 2025Article
- How Electricity Prevents Us from Bleeding to Death.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.Nature microbiology · 2024Article
- The controversial effect of smoking and nicotine in SARS-CoV-2 infection.Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology · 2023Review
- The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis.ACS omega · 2022Article
- Structurally Modified Bioactive Peptide Inhibits SARS-CoV-2 Lentiviral Particles Expression.Pharmaceutics · 2022Article
- Andrographolide induces anti-SARS-CoV-2 response through host-directed mechanism: anFuture virology · 2022Article
- The Path to Therapeutic Furin Inhibitors: From Yeast Pheromones to SARS-CoV-2.International journal of molecular sciences · 2022Review
- Maturation of subtilisin-like protease NbSLP1 from microsporidiaFrontiers in cellular and infection microbiology · 2022Article
- The interactions of folate with the enzyme furin: a computational study.RSC advances · 2021Article
- Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza.Frontiers in molecular biosciences · 2021Review
- Does Covera-19 know 'when to hold 'em or 'when to fold 'em? A translational thought experiment.Translational medicine communications · 2021Review
- Can endolysosomal deacidification and inhibition of autophagy prevent severe COVID-19?Life sciences · 2020Review
- Furin: A Potential Therapeutic Target for COVID-19.iScience · 2020Article
- A comprehensive review about SARS-CoV-2.Future virology · 2020Review
- Lowering the increased intracellular pH of human-induced pluripotent stem cell-derived endothelial cells induces formation of mature Weibel-Palade bodies.Stem cells translational medicine · 2020Article
- Do proteolytic cascades exist in plants?Journal of experimental botany · 2019Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
The folding and activation of furin occur through two pH- and compartment-specific autoproteolytic steps. In the endoplasmic reticulum (ER), profurin folds under the guidance of its prodomain and undergoes an autoproteolytic excision at the consensus furin site Arg-Thr-Lys-Arg107/ generating an enzymatically masked furin-propeptide complex competent for transport to late secretory compartments. In the mildly acidic environment of the trans-Golgi network/endosomal system, the bound propeptide is cleaved at the internal site 69HRGVTKR75/, unmasking active furin capable of cleaving substrates in trans. Here, by using cellular, biochemical, and modeling studies, we demonstrate that the conserved His69 is a pH sensor that regulates the compartment-specific cleavages of the propeptide. In the ER, unprotonated His69 stabilizes a solvent-accessible hydrophobic pocket necessary for autoproteolytic excision at Arg107. Profurin molecules unable to form the hydrophobic pocket, and hence, the furin-propeptide complex, are restricted to the ER by a PACS-2- and COPI-dependent mechanism. Once exposed to the acidic pH of the late secretory pathway, protonated His69 disrupts the hydrophobic pocket, resulting in exposure and cleavage of the internal cleavage site at Arg75 to unmask the enzyme. Together, our data explain the pH-regulated activation of furin and how this His-dependent regulatory mechanism is a model for other proteins.
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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.