ArticleThe Journal of biological chemistry2014
Sequence and conformational specificity in substrate recognition: several human Kunitz protease inhibitor domains are specific substrates of mesotrypsin.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- Hepatocyte growth factor activator inhibitor-2 rapidly inactivates airway-expressed human type II transmembrane serine proteases.The Journal of biological chemistry · 2026Article
- Membrane-Anchored Serine Protease Inhibitors: Physiological Functions, Mechanisms, and Roles in Cancer.International journal of molecular sciences · 2026Review
- Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.Science advances · 2025Article
- Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes.International journal of molecular sciences · 2024Article
- Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers.Molecular oncology · 2023Article
- Shear Stress Drives the Cleavage Activation of Protease-Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- The roles of proteases in prostate cancer.IUBMB life · 2023Review
- Climbing Up and Down Binding Landscapes through Deep Mutational Scanning of Three Homologous Protein-Protein Complexes.Journal of the American Chemical Society · 2021Article
- Mouse model suggests limited role for human mesotrypsin in pancreatitis.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2021Article
- Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site.PloS one · 2021Article
- The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2020Review
- Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz-Domain Inhibitors.Journal of molecular evolution · 2020Review
- Inactivation of mesotrypsin by chymotrypsin C prevents trypsin inhibitor degradation.The Journal of biological chemistry · 2020Article
- Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin.The Journal of biological chemistry · 2019Article
- PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma.Scientific reports · 2019Article
- Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.The Biochemical journal · 2018Article
- The Kunitz Domain I of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells.Scientific reports · 2017Article
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- An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis.The Journal of biological chemistry · 2016Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Mesotrypsin is an isoform of trypsin that is uniquely resistant to polypeptide trypsin inhibitors and can cleave some inhibitors rapidly. Previous studies have shown that the amyloid precursor protein Kunitz protease inhibitor domain (APPI) is a specific substrate of mesotrypsin and that stabilization of the APPI cleavage site in a canonical conformation contributes to recognition by mesotrypsin. We hypothesized that other proteins possessing potential cleavage sites stabilized in a similar conformation might also be mesotrypsin substrates. Here we evaluated a series of candidate substrates, including human Kunitz protease inhibitor domains from amyloid precursor-like protein 2 (APLP2), bikunin, hepatocyte growth factor activator inhibitor type 2 (HAI2), tissue factor pathway inhibitor-1 (TFPI1), and tissue factor pathway inhibitor-2 (TFPI2), as well as E-selectin, an unrelated protein possessing a potential cleavage site displaying canonical conformation. We find that Kunitz domains within APLP2, bikunin, and HAI2 are cleaved by mesotrypsin with kinetic profiles of specific substrates. TFPI1 and TFPI2 Kunitz domains are cleaved less efficiently by mesotrypsin, and E-selectin is not cleaved at the anticipated site. Cocrystal structures of mesotrypsin with HAI2 and bikunin Kunitz domains reveal the mode of mesotrypsin interaction with its canonical substrates. Our data suggest that major determinants of mesotrypsin substrate specificity include sequence preferences at the P1 and P'2 positions along with conformational stabilization of the cleavage site in the canonical conformation. Mesotrypsin up-regulation has been implicated previously in cancer progression, and proteolytic clearance of Kunitz protease inhibitors offers potential mechanisms by which mesotrypsin may mediate pathological effects in cancer.
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