ArticleBiochemistry2012
Energetic and structural basis for activation of the epithelial sodium channel by matriptase.
Article in Biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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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
22 citing papers in PubMed, 27 citations in OpenAlex.
- The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives.Journal of molecular biology · 2025Review
- Influence of proteolytic cleavage of ENaC's γ subunit upon NaAmerican journal of physiology. Renal physiology · 2024Article
- Epithelial NaComprehensive Physiology · 2024Review
- Article
- The genetics of monogenic intestinal epithelial disorders.Human genetics · 2023Review
- The Epithelial Sodium Channel-An Underestimated Drug Target.International journal of molecular sciences · 2023Review
- Transmembrane serine protease 2 (TMPRSS2) proteolytically activates the epithelial sodium channel (ENaC) by cleaving the channel's γ-subunit.The Journal of biological chemistry · 2022Article
- ENaC activation by proteases.Acta physiologica (Oxford, England) · 2022Review
- Proteolytic ENaC activation in health and disease-a complicated puzzle.Pflugers Archiv : European journal of physiology · 2022Article
- The epithelial NaThe Journal of biological chemistry · 2018Article
- The N terminus of α-ENaC mediates ENaC cleavage and activation by furin.The Journal of general physiology · 2018Article
- Epithelial NaAnnual review of physiology · 2018Review
- The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19.British journal of pharmacology · 2016Review
- Applications of Discrete Molecular Dynamics in biology and medicine.Current opinion in structural biology · 2016Review
- Gain-of-Function Mutation W493R in the Epithelial Sodium Channel Allosterically Reconfigures Intersubunit Coupling.The Journal of biological chemistry · 2016Article
- Sodium retention and volume expansion in nephrotic syndrome: implications for hypertension.Advances in chronic kidney disease · 2015Review
- The N-terminal domain allosterically regulates cleavage and activation of the epithelial sodium channel.The Journal of biological chemistry · 2014Article
- Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells.Nature reviews. Nephrology · 2014Review
- Gene expression correlations in human cancer cell lines define molecular interaction networks for epithelial phenotype.PloS one · 2014Article
- Acid-mediated tumor proteolysis: contribution of cysteine cathepsins.Neoplasia (New York, N.Y.) · 2013Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Limited proteolysis, accomplished by endopeptidases, is a ubiquitous phenomenon underlying the regulation and activation of many enzymes, receptors, and other proteins synthesized as inactive precursors. Serine proteases make up one of the largest and most conserved families of endopeptidases involved in diverse cellular activities, including wound healing, blood coagulation, and immune responses. Heteromeric α,β,γ-epithelial sodium channels (ENaC) associated with diseases like cystic fibrosis and Liddle's syndrome are irreversibly stimulated by membrane-anchored proteases (MAPs) and furin-like convertases. Matriptase/channel activating protease-3 (CAP3) is one of the several MAPs that potently activate ENaC. Despite identification of protease cleavage sites, the basis for the enhanced susceptibility of α- and γ-ENaC to proteases remains elusive. Here, we elucidate the energetic and structural bases for activation of ENaC by CAP3. We find a region near the γ-ENaC furin site that has previously not been identified as a critical cleavage site for CAP3-mediated stimulation. We also report that CAP3 mediates cleavage of ENaC at basic residues downstream of the furin site. Our results indicate that surface proteases alone are sufficient to fully activate uncleaved ENaC and explain how ENaC in epithelia expressing surface-active proteases can appear refractory to soluble proteases. Our results support a model in which proteases prime ENaC for activation by cleaving at the furin site, and cleavage at downstream sites is accomplished by membrane surface proteases or extracellular soluble proteases. On the basis of our results, we propose a dynamics-driven "anglerfish" mechanism that explains less stringent sequence requirements for substrate recognition and cleavage by matriptase than by furin.
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What OpenQuestion holds
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.