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Structural and functional studies of C4b-binding protein (C4BP)

Kask, Lena LU (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:
author
opponent
  • Prof Barlow, Paul
organization
publishing date
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
ISBN
91-628-6055-0
language
English
LU publication?
yes
id
0a26eb0e-6cf1-4f72-bacb-b1668d5a1470 (old id 467016)
date added to LUP
2007-09-07 14:07:41
date last changed
2016-09-19 08:45:07
@misc{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},
  keyword      = {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},
  pages        = {130},
  publisher    = {ARRAY(0xc2113c8)},
  title        = {Structural and functional studies of C4b-binding protein (C4BP)},
  year         = {2004},
}