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Studies on the interaction between vitamin K-dependent protein S and complement regulator C4b-binding protein: localization of binding sites and identification of a possible function of the complex.

Webb, Joanna LU (2002) In Scandinavian journal of clinical and laboratory investigation 62(Suppl 237). p.19-28
Abstract
Complement is a cascade-like system that is part of the innate immune defence. It is an explosive system, potentially harmful also for the host cells, and needs to be strictly regulated. An important down-regulator of complement is C4b-binding protein (C4BP). C4BP contains two different types of subunits, seven identical a-chains and one unique P-chain. The alpha-chains bind to C4b, C4BP's target in the complement system. The P-chain binds to vitamin K-dependent protein S. Approximately 70% of all protein S in plasma circulates in a high affinity complex with C4BP. Free protein S, the remaining 30%, functions as an important cofactor in the anticoagulant system. The reason for the complex formation between C413P and protein S has remained... (More)
Complement is a cascade-like system that is part of the innate immune defence. It is an explosive system, potentially harmful also for the host cells, and needs to be strictly regulated. An important down-regulator of complement is C4b-binding protein (C4BP). C4BP contains two different types of subunits, seven identical a-chains and one unique P-chain. The alpha-chains bind to C4b, C4BP's target in the complement system. The P-chain binds to vitamin K-dependent protein S. Approximately 70% of all protein S in plasma circulates in a high affinity complex with C4BP. Free protein S, the remaining 30%, functions as an important cofactor in the anticoagulant system. The reason for the complex formation between C413P and protein S has remained an intriguing enigma. Protein S has a very high affinity to negatively charged phospholipids for protein S. One area where such phospholipids are present is the surface of the apoptotic cell, where the exposure of phosphatidylserine is an early event. Physiological apoptosis is characterized by a lack of inflammatory response in surrounding tissues, indicating that cells are rapidly cleared before leaking cytoplasmic components into the extracellular space. A number of studies demonstrate that early complement proteins are important for the removal of apoptotic cells, but that subsequent assembly of later complement components and anaphylatoxin release must be prohibited in order not to provoke an inflammatory response. We demonstrate that protein S localizes C4BP to the surface of apoptotic cells via binding to the exposed phosphatidylserine. The C4BP attached to the apoptotic cell through protein S was still able to bind C4b, suggesting that C413P retains its physiological function also when localized to the apoptotic cell surface. In addition, we have also pinpointed a hydrophobic binding site for protein S on C4BP. The binding studies between C413P and protein S were performed on recombinant proteins where mutations had been introduced. Mutations were chosen based on a 3D-homology model of the C4BP P-chain. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
binding site, protein S, apoptosis, C4b-binding protein, complement
in
Scandinavian journal of clinical and laboratory investigation
volume
62
issue
Suppl 237
pages
19 - 28
publisher
Taylor & Francis
external identifiers
  • wos:000180064200005
  • scopus:0036460546
ISSN
0085-591X
DOI
10.1080/003655102762377457
language
English
LU publication?
yes
id
a72f87a0-4216-4eb4-b241-7bc0496f009b (old id 114472)
date added to LUP
2007-07-27 12:36:59
date last changed
2017-01-01 07:08:44
@article{a72f87a0-4216-4eb4-b241-7bc0496f009b,
  abstract     = {Complement is a cascade-like system that is part of the innate immune defence. It is an explosive system, potentially harmful also for the host cells, and needs to be strictly regulated. An important down-regulator of complement is C4b-binding protein (C4BP). C4BP contains two different types of subunits, seven identical a-chains and one unique P-chain. The alpha-chains bind to C4b, C4BP's target in the complement system. The P-chain binds to vitamin K-dependent protein S. Approximately 70% of all protein S in plasma circulates in a high affinity complex with C4BP. Free protein S, the remaining 30%, functions as an important cofactor in the anticoagulant system. The reason for the complex formation between C413P and protein S has remained an intriguing enigma. Protein S has a very high affinity to negatively charged phospholipids for protein S. One area where such phospholipids are present is the surface of the apoptotic cell, where the exposure of phosphatidylserine is an early event. Physiological apoptosis is characterized by a lack of inflammatory response in surrounding tissues, indicating that cells are rapidly cleared before leaking cytoplasmic components into the extracellular space. A number of studies demonstrate that early complement proteins are important for the removal of apoptotic cells, but that subsequent assembly of later complement components and anaphylatoxin release must be prohibited in order not to provoke an inflammatory response. We demonstrate that protein S localizes C4BP to the surface of apoptotic cells via binding to the exposed phosphatidylserine. The C4BP attached to the apoptotic cell through protein S was still able to bind C4b, suggesting that C413P retains its physiological function also when localized to the apoptotic cell surface. In addition, we have also pinpointed a hydrophobic binding site for protein S on C4BP. The binding studies between C413P and protein S were performed on recombinant proteins where mutations had been introduced. Mutations were chosen based on a 3D-homology model of the C4BP P-chain.},
  author       = {Webb, Joanna},
  issn         = {0085-591X},
  keyword      = {binding site,protein S,apoptosis,C4b-binding protein,complement},
  language     = {eng},
  number       = {Suppl 237},
  pages        = {19--28},
  publisher    = {Taylor & Francis},
  series       = {Scandinavian journal of clinical and laboratory investigation},
  title        = {Studies on the interaction between vitamin K-dependent protein S and complement regulator C4b-binding protein: localization of binding sites and identification of a possible function of the complex.},
  url          = {http://dx.doi.org/10.1080/003655102762377457},
  volume       = {62},
  year         = {2002},
}