The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Substrate Profiling of Cysteine Proteases Using a Combinatorial Peptide Library Identifies Functionally Unique Specificities
Open accessAbstract
The substrate specificities of papain-like cysteine proteases (clan CA, family C1) papain, bromelain, and human cathepsins L, V, K, S, F, B, and five proteases of parasitic origin were studied using a completely diversified positional scanning synthetic combinatorial library. A bifunctional coumarin fluorophore was used that facilitated synthesis of the library and individual peptide substrates. The library has a total of 160,000 tetrapeptide substrate sequences completely randomizing each of the P1, P2, P3, and P4 positions with 20 amino acids. A microtiter plate assay format permitted a rapid determination of the specificity profile of each enzyme. Individual peptide substrates were then synthesized and tested for a quantitative determination of the specificity of the human cathepsins. Despite the conserved three-dimensional structure and similar substrate specificity of the enzymes studied, distinct amino acid preferences that differentiate each enzyme were identified. The specificities of cathepsins K and S partially match the cleavage site sequences in their physiological substrates. Capitalizing on its unique preference for proline and glycine at the P2 and P3 positions, respectively, selective substrates and a substrate-based inhibitor were developed for cathepsin K. A cluster analysis of the proteases based on the complete specificity profile provided a functional characterization distinct from standard sequence analysis. This approach provides useful information for developing selective chemical probes to study protease-related pathologies and physiologies.
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Cluster analysis and display of genome-wide expression patterns
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Leontovyč, A., Ulrychová, L., O’Donoghue, A. J., Vondrášek, J., Marešová, L., Hubálek, M., Fajtová, P., Chanová, M., Jiang, Z., Craik, C. S., et al. (2018) · PLOS Neglected Tropical Diseases · doi:10.1371/journal.pntd.0006446 · Cited by 45
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Metadata
- Authors
- Choe, Y., Leonetti, F., Greenbaum, D. C., Lecaille, F., Bogyo, M., Brömme, D., Ellman, J. A., & Craik, C. S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 281
- Issue
- 18
- Pages
- 12824-12832
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2012845953
- Cited by
- 425
- References
- 1
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
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