ArticlePloS one2014
Cleavage specificity analysis of six type II transmembrane serine proteases (TTSPs) using PICS with proteome-derived peptide libraries.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 59 citations in OpenAlex.
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- Engineering high-efficiency matriptase substrates using E. coli display for applications in prodrug activation.Cell reports methods · 2025Article
- From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants.Journal of medicinal chemistry · 2025Article
- Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency.bioRxiv : the preprint server for biology · 2024Article
- Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin.Protein science : a publication of the Protein Society · 2024Article
- Proteolysis of vaginally administered bovine lactoferrin: clearance, inter-subject variability, and implications for clinical dosing.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2023Article
- Initial detachment of the mouse oocyte from the zona pellucida is mediated by metallopeptidase activity†.Biology of reproduction · 2023Article
- TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation.Journal of medical genetics · 2022Review
- The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment.International journal of molecular sciences · 2022Review
- Characterization of proteolytic degradation products of vaginally administered bovine lactoferrin.PloS one · 2022Article
- Cryo-EM structure of native human uromodulin, a zona pellucida module polymer.The EMBO journal · 2020Article
- COVID-19 Coronavirus spike protein analysis for synthetic vaccines, a peptidomimetic antagonist, and therapeutic drugs, and analysis of a proposed achilles' heel conserved region to minimize probability of escape mutations and drug resistance.Computers in biology and medicine · 2020Review
- Potential Therapeutic Targeting of Coronavirus Spike Glycoprotein Priming.Molecules (Basel, Switzerland) · 2020Article
- Computers and viral diseases. Preliminary bioinformatics studies on the design of a synthetic vaccine and a preventative peptidomimetic antagonist against the SARS-CoV-2 (2019-nCoV, COVID-19) coronavirus.Computers in biology and medicine · 2020Article
- Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids.Stem cell reports · 2019Article
- TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer.Cell biology international · 2018Article
- The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover.Scientific reports · 2017Article
- Proteolytic processing of lysyl oxidase-like-2 in the extracellular matrix is required for crosslinking of basement membrane collagen IV.The Journal of biological chemistry · 2017Article
- Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella.Nature communications · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundType II transmembrane serine proteases (TTSPs) are a family of cell membrane tethered serine proteases with unclear roles as their cleavage site specificities and substrate degradomes have not been fully elucidated. Indeed just 52 cleavage sites are annotated in MEROPS, the database of proteases, their substrates and inhibitors. METHODOLOGY/PRINCIPAL FINDING: To profile the active site specificities of the TTSPs, we applied Proteomic Identification of protease Cleavage Sites (PICS). Human proteome-derived database searchable peptide libraries were assayed with six human TTSPs (matriptase, matriptase-2, matriptase-3, HAT, DESC and hepsin) to simultaneously determine sequence preferences on the N-terminal non-prime (P) and C-terminal prime (P') sides of the scissile bond. Prime-side cleavage products were isolated following biotinylation and identified by tandem mass spectrometry. The corresponding non-prime side sequences were derived from human proteome databases using bioinformatics. Sequencing of 2,405 individual cleaved peptides allowed for the development of the family consensus protease cleavage site specificity revealing a strong specificity for arginine in the P1 position and surprisingly a lysine in P1' position. TTSP cleavage between R↓K was confirmed using synthetic peptides. By parsing through known substrates and known structures of TTSP catalytic domains, and by modeling the remainder, structural explanations for this strong specificity were derived.
conclusionsDegradomics analysis of 2,405 cleavage sites revealed a similar and characteristic TTSP family specificity at the P1 and P1' positions for arginine and lysine in unfolded peptides. The prime side is important for cleavage specificity, thus making these proteases unusual within the tryptic-enzyme class that generally has overriding non-prime side specificity.
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Registered trials
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