Defining the extended substrate specificity of kallikrein 1-related peptidases
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Carla A. Borgoño
Abstract
Human kallikrein 1-related peptidases (KLKs) form a subfamily of 15 extracellular (chymo)tryptic-like serine proteases. KLKs 4, 5, 13 and 14 display altered expression/activity in diverse pathological conditions, including cancer. However, their distinct (patho)physiological roles remain largely uncharacterized. As a step toward distinguishing their proteolytic functions, we attempt to define their primary and extended substrate specificities and identify candidate biological targets. Heterologously expressed KLKs 4, 5, 13 and 14 were screened against fluorogenic 7-amino-4-carbamoylmethylcoumarin positional scanning-synthetic combinatorial libraries with amino acid diversity at the P1–P4 positions. Our results indicate that these KLKs share a P1 preference for Arg. However, each KLK exhibited distinct P2–P4 specificities, attributable to structural variations in their surface loops. The preferred P4–P1 substrate recognition motifs based on optimal subsite occupancy were as follows: VI-QSAV-QL-R for KLK4; YFWGPV-RK-NSFAM-R for KLK5; VY-R-LFM-R for KLK13; and YW-KRSAM-HNSPA-R for KLK14. Protein database queries using these motifs yielded many extracellular targets, some of which represent plausible KLK substrates. For instance, cathelicidin, urokinase-type plasminogen activator, laminin and transmembrane protease serine 3 were retrieved as novel putative substrates for KLK4, 5, 13 and 14, respectively. Our findings may facilitate studies on the role of KLKs in (patho)physiology and can be used in the development of selective KLK inhibitors.
©2007 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Proteinase Inhibitors and Biological Control – An Attractive International Symposia Series
- Two decades of thyroglobulin type-1 domain research
- Cysteine cathepsin non-inhibitory binding partners: modulating intracellular trafficking and function
- Cysteine proteases: destruction ability versus immunomodulation capacity in immune cells
- ‘Species’ of peptidases
- Protease research in the era of systems biology
- Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities
- Association of cathepsin E with tumor growth arrest through angiogenesis inhibition and enhanced immune responses
- Characterization and comparative 3D modeling of CmPI-II, a novel ‘non-classical’ Kazal-type inhibitor from the marine snail Cenchritis muricatus (Mollusca)
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- Characterisation of zinc-binding domains of peroxisomal RING finger proteins using size exclusion chromatography/inductively coupled plasma-mass spectrometry
- Defining the extended substrate specificity of kallikrein 1-related peptidases
- Latent MMP-9 is bound to TIMP-1 before secretion
- Novel expression of kallikreins, kallikrein-related peptidases and kinin receptors in human pleural mesothelioma
- Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease
- Clinical chemistry reference database for Wistar rats and C57/BL6 mice
