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Extended Cleavage Specificities of Rabbit and Guinea Pig Mast Cell Chymases: Two Highly Specific Leu-Ases

1
Department of Cell and Molecular Biology, Uppsala University, Uppsala, The Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden
2
GDL Pharmaceutical Consulting and Contracting, Downingtown, PA 19335, USA
3
Tosoh Bioscience LLC, 3604 Horizon Drive, King of Prussia, PA 19406, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6340; https://doi.org/10.3390/ijms20246340
Received: 19 November 2019 / Revised: 10 December 2019 / Accepted: 13 December 2019 / Published: 16 December 2019
Serine proteases constitute the major protein content of mast cell (MC) secretory granules. These proteases can generally be subdivided into chymases and tryptases based on their primary cleavage specificity. Here, we presented the extended cleavage specificities of a rabbit β-chymase and a guinea pig α-chymase. Analyses by phage display screening and a panel of recombinant substrates showed a marked similarity in catalytic activity between the enzymes, both being strict Leu-ases (cleaving on the carboxyl side of Leu). Amino acid sequence alignment of a panel of mammalian chymotryptic MC proteases and 3D structural modeling identified an unusual residue in the rabbit enzyme at position 216 (Thr instead of more common Gly), which is most likely critical for the Leu-ase specificity. Almost all mammals studied, except rabbit and guinea pig, express classical chymotryptic enzymes with similarly extended specificities, indicating an important role of chymase in MC biology. The rabbit and guinea pig are the only two mammalian species currently known to lack a classical MC chymase. Key questions are now how this major difference affects their MC function, and if genes of other loci can rescue the loss of a chymotryptic activity in MCs of these two species. View Full-Text
Keywords: mast cells; chymase; tryptase; cleavage specificity; Leu-ase; phage display mast cells; chymase; tryptase; cleavage specificity; Leu-ase; phage display
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Zhongwei, Y.; Akula, S.; Fu, Z.; de Garavilla, L.; Kervinen, J.; Thorpe, M.; Hellman, L. Extended Cleavage Specificities of Rabbit and Guinea Pig Mast Cell Chymases: Two Highly Specific Leu-Ases. Int. J. Mol. Sci. 2019, 20, 6340.

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