ArticleCell2013
Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity.
Article in Cell, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 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.
The trial behind it
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
66 citing papers in PubMed, 123 citations in OpenAlex.
- Rhomboid Proteases in Plasmodium spp. : Biology, Functional Roles, and Therapeutic Potential.Acta parasitologica · 2026Review
- Cardiolipin Modulates the Activity of the Intramembrane Protease GlpG Inducing Membrane Restructuring.Journal of the American Chemical Society · 2026Article
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Conformational Flexibility of Transmembrane Helices: How it Works and Where it Matters.Chemical reviews · 2026Review
- Protease regulation of tumor-immune cell symbiosis.Trends in cancer · 2025Review
- Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.Chembiochem : a European journal of chemical biology · 2025Review
- Evaluating the impact of the membrane thickness on the function of the intramembrane protease GlpG.Biophysical journal · 2024Article
- Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.Computational and structural biotechnology journal · 2024Article
- AnbioRxiv : the preprint server for biology · 2024Article
- Dynamic association of the intramembrane proteases SPPL2a/b and their substrates with tetraspanin-enriched microdomains.iScience · 2023Article
- Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase.Communications biology · 2023Article
- Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy.Journal of medicinal chemistry · 2023Article
- Rhomboid-catalyzed intramembrane proteolysis requires hydrophobic matching with the surrounding lipid bilayer.Science advances · 2022Article
- Mechanistic insights into intramembrane proteolysis byScience advances · 2022Article
- Article
- Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis.Nature communications · 2022Article
- Article
- Effect of Environmental Factors on the Catalytic Activity of Intramembrane Serine Protease.Journal of the American Chemical Society · 2022Article
- OMA1-An integral membrane protease?Biochimica et biophysica acta. Proteins and proteomics · 2021Review
- Decoding the Functional Evolution of an Intramembrane Protease Superfamily by Statistical Coupling Analysis.Structure (London, England : 1993) · 2020Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Enzymatic cleavage of transmembrane anchors to release proteins from the membrane controls diverse signaling pathways and is implicated in more than a dozen diseases. How catalysis works within the viscous, water-excluding, two-dimensional membrane is unknown. We developed an inducible reconstitution system to interrogate rhomboid proteolysis quantitatively within the membrane in real time. Remarkably, rhomboid proteases displayed no physiological affinity for substrates (K(d) ~190 μM/0.1 mol%). Instead, ~10,000-fold differences in proteolytic efficiency with substrate mutants and diverse rhomboid proteases were reflected in k(cat) values alone. Analysis of gate-open mutant and solvent isotope effects revealed that substrate gating, not hydrolysis, is rate limiting. Ultimately, a single proteolytic event within the membrane normally takes minutes. Rhomboid intramembrane proteolysis is thus a slow, kinetically controlled reaction not driven by transmembrane protein-protein affinity. These properties are unlike those of other studied proteases or membrane proteins but are strikingly reminiscent of one subset of DNA-repair enzymes, raising important mechanistic and drug-design implications.
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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.