ArticleThe Journal of biological chemistry2015
Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.Science advances · 2025Article
- PRSS3/mesotrypsin as a putative regulator of the biophysical characteristics of epidermal keratinocytes in superficial layers.Scientific reports · 2024Article
- Serine protease inhibitors decrease metastasis in prostate, breast, and ovarian cancers.Molecular oncology · 2023Article
- Potent Inhibitor of Human Trypsins from the Aeruginosin Family of Natural Products.ACS chemical biology · 2021Article
- 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
- Inactivation of mesotrypsin by chymotrypsin C prevents trypsin inhibitor degradation.The Journal of biological chemistry · 2020Article
- Elevated β-cell stress levels promote severe diabetes development in mice with MODY4.The Journal of endocrinology · 2020Article
- Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis.Journal of pancreatic cancer · 2020Review
- 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
- Proteases: Pivot Points in Functional Proteomics.Methods in molecular biology (Clifton, N.J.) · 2019Review
- Mapping protein selectivity landscapes using multi-target selective screening and next-generation sequencing of combinatorial libraries.Nature communications · 2018Article
- Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.The Biochemical journal · 2018Article
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- An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis.The Journal of biological chemistry · 2016Article
- Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy.The Biochemical journal · 2016Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Human mesotrypsin is highly homologous to other mammalian trypsins, and yet it is functionally unique in possessing resistance to inhibition by canonical serine protease inhibitors and in cleaving these inhibitors as preferred substrates. Arg-193 and Ser-39 have been identified as contributors to the inhibitor resistance and cleavage capability of mesotrypsin, but it is not known whether these residues fully account for the unusual properties of mesotrypsin. Here, we use human cationic trypsin as a template for engineering a gain of catalytic function, assessing mutants containing mesotrypsin-like mutations for resistance to inhibition by bovine pancreatic trypsin inhibitor (BPTI) and amyloid precursor protein Kunitz protease inhibitor (APPI), and for the ability to hydrolyze these inhibitors as substrates. We find that Arg-193 and Ser-39 are sufficient to confer mesotrypsin-like resistance to inhibition; however, compared with mesotrypsin, the trypsin-Y39S/G193R double mutant remains 10-fold slower at hydrolyzing BPTI and 2.5-fold slower at hydrolyzing APPI. We identify two additional residues in mesotrypsin, Lys-74 and Asp-97, which in concert with Arg-193 and Ser-39 confer the full catalytic capability of mesotrypsin for proteolysis of BPTI and APPI. Novel crystal structures of trypsin mutants in complex with BPTI suggest that these four residues function cooperatively to favor conformational dynamics that assist in dissociation of cleaved inhibitors. Our results reveal that efficient inhibitor cleavage is a complex capability to which at least four spatially separated residues of mesotrypsin contribute. These findings suggest that inhibitor cleavage represents a functional adaptation of mesotrypsin that may have evolved in response to positive selection pressure.
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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.