Structural and functional studies of C4b-binding protein (C4BP)
(2004)- Abstract
- The subject of this thesis is complement inhibitor C4b-binding protein (C4BP), on which we have performed both structural and functional studies. Complement is part of the innate immune defence and eliminates microbes, solubilises immune complexes and is involved in the clearance of apoptotic cells. The actions of the complement system must be carefully controlled by proteins such as C4BP to avoid self-damage of the host. C4BP is a polymeric protein composed of seven identical alpha-chains and one beta-chain. In human plasma, C4BP circulates in complex with protein S (PS), a cofactor in the anticoagulant system. The alpha-chains of C4BP bind C4b and thereby inhibit the actions of this activated complement factor in the classical pathway of... (More)
- The subject of this thesis is complement inhibitor C4b-binding protein (C4BP), on which we have performed both structural and functional studies. Complement is part of the innate immune defence and eliminates microbes, solubilises immune complexes and is involved in the clearance of apoptotic cells. The actions of the complement system must be carefully controlled by proteins such as C4BP to avoid self-damage of the host. C4BP is a polymeric protein composed of seven identical alpha-chains and one beta-chain. In human plasma, C4BP circulates in complex with protein S (PS), a cofactor in the anticoagulant system. The alpha-chains of C4BP bind C4b and thereby inhibit the actions of this activated complement factor in the classical pathway of complement. Our structural studies include determination of binding sites for C4b, C3b and heparin, structural requirements for the polymerisation of C4BP, and the structural stability of C4BP in adverse conditions. Based on the understanding of the polymerisation of C4BP we propose how to use the core of C4BP in the production of multimeric biotechnological tools. There is a need for therapeutic complement inhibitors, and the knowledge of the mechanisms of inhibition and the structural stability of natural complement inhibitors will be helpful in development of such drugs. The functional studies we have performed demonstrate the ability of C4BP to bind C3b and present it for degradation, thereby inhibiting the alternative pathway of complement, enhancement of C4BP activity in the presence of zinc and the role of C4BP in the phagocytosis of apoptotic cells. We found that the C4BP-PS complex inhibits phagocytosis of apoptotic cells by macrophages, suggesting an important physiological role for the complex. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/467016
- author
- Kask, Lena LU
- supervisor
- opponent
-
- Prof Barlow, Paul
- organization
- publishing date
- 2004
- type
- Thesis
- publication status
- published
- subject
- keywords
- phagocytosis, apoptosis, protein S, complement control protein (CCP) domains, factor H (fH), Complement, C4b-binding protein (C4BP), intracellular assembly, Clinical chemistry, Klinisk kemi
- pages
- 130 pages
- publisher
- Lena Kask, Wallenberg Laboratory, floor 6, entrance 46, UMAS, S-205 02 Malmö,
- defense location
- Jubileumsaulan, Medicinskt forskningscentrum, ingång 59, UMAS, Malmö
- defense date
- 2004-05-27 09:15:00
- ISBN
- 91-628-6055-0
- language
- English
- LU publication?
- yes
- additional info
- Article: I Blom A. M., Kask L. and Dahlbäck B. Structural requirements for the complement regulatory activities of C4BP, J. Biol. Chem. 2001 276 (29):27136-44 Article: II Kask L., Hillarp A., Ramesh B., Dahlbäck B. and Blom A. M. Structural requirements for the intracellular subunit polymerization of the complement inhibitor C4b-binding protein, Biochemistry 2002 Jul 30;41(30):9349-57. Article: III Blom A. M., Kask L. and Dahlbäck B. CCP1-4 of the C4b-binding protein alpha-chain are required for factor I mediated cleavage of complement factor C3b. Mol Immunol. 2003 Jan;39 (10):547-56. Article: IV Blom A. M., Kask L., Ramesh B. and Hillarp A.Effects of zinc on factor I cofactor activity of C4b-binding protein and factor H, Arch Biochem Biophys. 2003 Oct 15;418 (2):108-18. Article: V Kask L., Villoutreix B. O., Steen M., Ramesh B., Dahlbäck B. and Blom A. M. Structural stability and heat-induced conformational change of two complement inhibitors: C4b-binding protein and factor H. Protein Science 2003 in press Article: VI Kask L., Trouw L. A., Dahlbäck B. and Blom A. M. The C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells. J. Biol. Chem. 2004 in press
- id
- 0a26eb0e-6cf1-4f72-bacb-b1668d5a1470 (old id 467016)
- date added to LUP
- 2016-04-04 10:51:54
- date last changed
- 2018-11-21 21:01:13
@phdthesis{0a26eb0e-6cf1-4f72-bacb-b1668d5a1470,
abstract = {{The subject of this thesis is complement inhibitor C4b-binding protein (C4BP), on which we have performed both structural and functional studies. Complement is part of the innate immune defence and eliminates microbes, solubilises immune complexes and is involved in the clearance of apoptotic cells. The actions of the complement system must be carefully controlled by proteins such as C4BP to avoid self-damage of the host. C4BP is a polymeric protein composed of seven identical alpha-chains and one beta-chain. In human plasma, C4BP circulates in complex with protein S (PS), a cofactor in the anticoagulant system. The alpha-chains of C4BP bind C4b and thereby inhibit the actions of this activated complement factor in the classical pathway of complement. Our structural studies include determination of binding sites for C4b, C3b and heparin, structural requirements for the polymerisation of C4BP, and the structural stability of C4BP in adverse conditions. Based on the understanding of the polymerisation of C4BP we propose how to use the core of C4BP in the production of multimeric biotechnological tools. There is a need for therapeutic complement inhibitors, and the knowledge of the mechanisms of inhibition and the structural stability of natural complement inhibitors will be helpful in development of such drugs. The functional studies we have performed demonstrate the ability of C4BP to bind C3b and present it for degradation, thereby inhibiting the alternative pathway of complement, enhancement of C4BP activity in the presence of zinc and the role of C4BP in the phagocytosis of apoptotic cells. We found that the C4BP-PS complex inhibits phagocytosis of apoptotic cells by macrophages, suggesting an important physiological role for the complex.}},
author = {{Kask, Lena}},
isbn = {{91-628-6055-0}},
keywords = {{phagocytosis; apoptosis; protein S; complement control protein (CCP) domains; factor H (fH); Complement; C4b-binding protein (C4BP); intracellular assembly; Clinical chemistry; Klinisk kemi}},
language = {{eng}},
publisher = {{Lena Kask, Wallenberg Laboratory, floor 6, entrance 46, UMAS, S-205 02 Malmö,}},
school = {{Lund University}},
title = {{Structural and functional studies of C4b-binding protein (C4BP)}},
year = {{2004}},
}