ArticleThe Journal of biological chemistry2010
Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 47 citations in OpenAlex.
- Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.Science advances · 2025Article
- Identification of Kazal Inhibitor Scaffolds with Identical Canonical Binding Loops and Their Effects on Binding Properties.Biochemistry · 2023Article
- FGDB: a comprehensive graph database of ligand fragments from the Protein Data Bank.Database : the journal of biological databases and curation · 2022Article
- Structural and Biophysical Insights into SPINK1 Bound to Human Cationic Trypsin.International journal of molecular sciences · 2022Article
- 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
- Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin.The Journal of biological chemistry · 2019Article
- Epitope-specific affinity maturation improved stability of potent protease inhibitory antibodies.Biotechnology and bioengineering · 2018Article
- Mapping protein selectivity landscapes using multi-target selective screening and next-generation sequencing of combinatorial libraries.Nature communications · 2018Article
- A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering.The Journal of biological chemistry · 2018Article
- Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.The Biochemical journal · 2018Article
- The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition.The Journal of biological chemistry · 2017Article
- Article
- An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis.The Journal of biological chemistry · 2016Article
- A Camelid-derived Antibody Fragment Targeting the Active Site of a Serine Protease Balances between Inhibitor and Substrate Behavior.The Journal of biological chemistry · 2016Article
- Combinatorial protein engineering of proteolytically resistant mesotrypsin inhibitors as candidates for cancer therapy.The Biochemical journal · 2016Article
- Trypsinogen 4 boosts tumor endothelial cells migration through proteolysis of tissue factor pathway inhibitor-2.Oncotarget · 2015Article
- Mesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates.The Journal of biological chemistry · 2015Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
An important functional property of protein protease inhibitors is their stability to proteolysis. Mesotrypsin is a human trypsin that has been implicated in the proteolytic inactivation of several protein protease inhibitors. We have found that bovine pancreatic trypsin inhibitor (BPTI), a Kunitz protease inhibitor, inhibits mesotrypsin very weakly and is slowly proteolyzed, whereas, despite close sequence and structural homology, the Kunitz protease inhibitor domain of the amyloid precursor protein (APPI) binds to mesotrypsin 100 times more tightly and is cleaved 300 times more rapidly. To define features responsible for these differences, we have assessed the binding and cleavage by mesotrypsin of APPI and BPTI reciprocally mutated at two nonidentical residues that make direct contact with the enzyme. We find that Arg at P(1) (versus Lys) favors both tighter binding and more rapid cleavage, whereas Met (versus Arg) at P'(2) favors tighter binding but has minimal effect on cleavage. Surprisingly, we find that the APPI scaffold greatly enhances proteolytic cleavage rates, independently of the binding loop. We draw thermodynamic additivity cycles analyzing the interdependence of P(1) and P'(2) substitutions and scaffold differences, finding multiple instances in which the contributions of these features are nonadditive. We also report the crystal structure of the mesotrypsin·APPI complex, in which we find that the binding loop of APPI displays evidence of increased mobility compared with BPTI. Our data suggest that the enhanced vulnerability of APPI to mesotrypsin cleavage may derive from sequence differences in the scaffold that propagate increased flexibility and mobility to the binding loop.
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