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Channel catfish granzyme-like I is a highly specific serine protease with metase activity that is expressed by fish NK-like cells.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. (Lars Hellman)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
(English)Manuscript (preprint) (Other academic)
National Category
URN: urn:nbn:se:uu:diva-221554OAI: oai:DiVA.org:uu-221554DiVA: diva2:711292
Available from: 2014-04-09 Created: 2014-04-01 Last updated: 2014-05-13
In thesis
1. Haematopoietic Serine Proteases: A Cleavage Specificity Analysis
Open this publication in new window or tab >>Haematopoietic Serine Proteases: A Cleavage Specificity Analysis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells are innate immune cells, historically involved in allergy responses involving IgE. Through this, they have earned a reputation as a fairly detrimental cell type. Their beneficial roles remain somewhat enigmatic although they clearly have the ability to modulate the immune system. This is due to their ability to synthesise many cytokines and chemokines as well as immediately release potent granule-stored mediators. One such mediator is a serine protease, chymase, which has been targeted by pharmaceutical companies developing inhibitors for use in inflammatory conditions.

In order to address roles of the proteases, information regarding their cleavage specificity using substrate phage display can help find potential in vivo substrates.  The human chymase cleaves substrates with aromatic amino acids in the P1 position and has a preference for negatively charged amino acids in the P2’ position. The molecular interactions mediating this P2’ preference was investigated by site-directed mutagenesis, where Arg143 and Lys192 had a clear effect in this selectivity.

As humans express one chymase and rodents express multiple chymases, extrapolating data between species is difficult. Here, the crab-eating macaque was characterised, which showed many similarities to the human chymase including a near identical extended cleavage specificity and effects of human chymase inhibitors.  Appropriate models are needed when developing human inhibitors for therapeutic use in inflammatory conditions.

The effects of five specific chymase inhibitors in development were also tested. The selectivity of inhibitors was dependent on both Arg143 and Lys192, with a greater effect of Lys192. Identification of residues involved in specific inhibitor interactions is important for selective inhibitor development.

Another innate cell type, the NK cell, is important in virus and tumour defence. In the channel catfish, a serine protease from an NK-like cell, granzyme-like I, was characterised. A strict preference for Met in the P1 position was seen, and caspase 6 was identified as a potential in vivo target. This may highlight a novel apoptosis-inducing mechanism from a similar cell type has been conserved for approximately 400 myr.

Here, important residues mediating chymases’ specificity and interactions with inhibitors has been addressed, as well as finding a new animal model for providing ways to combat their roles in pathological settings.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1144
Mast cell, cleavage specificity, phage display, chymase, serine protease, granzyme, fish protease
National Category
urn:nbn:se:uu:diva-221891 (URN)978-91-554-8945-8 (ISBN)
Public defence
2014-06-04, C4:305, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2014-05-13 Created: 2014-04-07 Last updated: 2014-06-30Bibliographically approved

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