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The extended substrate recognition profile of the dog mast cell chymase reveals similarities and differences to the human chymase
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2010 (English)In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 22, no 6, 421-431 p.Article in journal (Refereed) Published
Abstract [en]

Human chymase (HC) constitutes a major granule protease in one of the two human mast cell (MC) types. The main biological role of this haematopoietic serine protease is probably not yet known, although it has been implicated in a large number of functions. Dogs, like humans, have only one chymase. This enzyme is closely related to its human homologue, and the MC subtypes of human and dog appear to be similar as well. Therefore, the functions of the dog chymase (DC) may closely reflect the functions of the HC. Moreover, dogs may serve as good models for studies of human MC functions and MC-related diseases. To reveal functional similarities and differences between the DC and HC, we have determined the extended cleavage specificity of the DC by substrate phage display. This method allows the simultaneous permutation of primed and unprimed substrate positions. The DC was found to have very similar preferences to its human counterpart for substrate positions P1, P3, P4 and P3', whereas their preferences differ at positions P2, P1' and P2'. Therefore, the HC and DC may have co-evolved with a substrate where positions P1, P3, P4 and P3' are conserved between dogs and humans, whereas positions P2 and P1' are not and P2' differs to a minor extent. The differences observed between these two enzymes suggest that results obtained from dog models cannot be directly extrapolated to human clinical settings but need to be evaluated carefully concerning potential differences in substrate preferences.

Place, publisher, year, edition, pages
2010. Vol. 22, no 6, 421-431 p.
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-95246DOI: 10.1093/intimm/dxq021ISI: 000279109000002OAI: oai:DiVA.org:uu-95246DiVA: diva2:169384
Available from: 2006-11-29 Created: 2006-11-29 Last updated: 2015-08-21
In thesis
1. Sculpted through Time: Evolution and Function of Serine Proteases from the Mast Cell Chymase Locus
Open this publication in new window or tab >>Sculpted through Time: Evolution and Function of Serine Proteases from the Mast Cell Chymase Locus
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Immune cells like NK cells, T cells, neutrophils and mast cells store high amounts of granule serine proteases, graspases. Graspases are encoded from the mast cell chymase locus. The human locus holds four genes: α-chymase, cathepsin G, and granzymes H and B. In contrast, the mouse locus contains at least 14 genes. Many of these belong to subfamilies not found in human, e.g. the Mcpt8-family. These differences hamper functional comparisons of graspases and of immune cells in the two species. Studies of the mast cell chymase locus are therefore important to better understand the mammalian immune system.

In this thesis, the evolution of the mast cell chymase locus was analysed by mapping the locus in all available mammalian genome sequences. It was revealed that one single ancestral gene founded this locus probably over 215 million years ago. This ancestor was duplicated more than 185 million years ago. One copy evolved into the α-chymases, whereas the second copy founded the families of granzymes B and H, cathepsin G, Mcpt8 and duodenases. Different subfamilies were later remarkably expanded in particular mammalian lineages, e.g. the Mcpt8- and Mcpt2-subfamilies in the rat. Four novel members of these families were identified in rat mucosal mast cells. Rat and mouse mast cells express numerous different graspases, whereas human and dog mast cells express only one graspase, chymase. To better understand mast cell functions in these species, one member of the mouse Mcpt8-family, mMCP-8, and human and dog chymase were studied. The preferred substrate sequence was analysed by substrate phage display. mMCP-8 remains yet enigmatic, although it is probably proteolytically active. Dog and human chymase, interestingly, have common preferences in certain substrate positions, but differ in others. These two chymases may have coevolved with an in vivo substrate that is conserved only in the positions with a common preference. We also obtained evidence that substrate positions on either side of the scissile bond influence each other. This kind of interactions can only be detected with a method investigating both sides simultaneously, such as substrate phage display.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 90 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 250
Immunology, immune system, mast cell, chymase locus, serine protease, evolution, gene duplication, Immunologi
urn:nbn:se:uu:diva-7379 (URN)91-554-6748-2 (ISBN)
Public defence
2006-12-20, C4:305, BMC, Husargatan 3, Uppsala, 09:00
Available from: 2006-11-29 Created: 2006-11-29Bibliographically approved

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Ge, Xueliang
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