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A novel interaction between complement inhibitor C4b-binding protein and plasminogen that enhances plasminogen activation.

Agarwal, Vaibhav LU ; Talens, Simone LU ; Grandits, Alexander M and Blom, Anna LU (2015) In Journal of Biological Chemistry 290(30). p.18333-18342
Abstract
The complement, coagulation and fibrinolytic systems are crucial for the maintenance of tissue homeostasis. To date numerous interactions and cross talks have been identified between these cascades. In line with this, here we propose a novel, hitherto unknown interaction between the complement inhibitor C4b-binding protein (C4BP) and plasminogen of the fibrinolytic pathway. Binding of C4BP to S. pneumoniae is a known virulence mechanism of this pathogen and it was increased in the presence of plasminogen. Interestingly, the acute phase variant of C4BP lacking the β-chain and protein S binds plasminogen much stronger than the main isoform containing the β-chain and protein S. Indeed, the complement control protein (CCP) 8 domain of C4BP,... (More)
The complement, coagulation and fibrinolytic systems are crucial for the maintenance of tissue homeostasis. To date numerous interactions and cross talks have been identified between these cascades. In line with this, here we propose a novel, hitherto unknown interaction between the complement inhibitor C4b-binding protein (C4BP) and plasminogen of the fibrinolytic pathway. Binding of C4BP to S. pneumoniae is a known virulence mechanism of this pathogen and it was increased in the presence of plasminogen. Interestingly, the acute phase variant of C4BP lacking the β-chain and protein S binds plasminogen much stronger than the main isoform containing the β-chain and protein S. Indeed, the complement control protein (CCP) 8 domain of C4BP, which would otherwise be sterically hindered by the β-chain, primarily mediates this interaction. Moreover, the lysine-binding sites in plasminogen kringle domains facilitate the C4BP-plasminogen interaction. Furthermore, C4BP readily forms complexes with plasminogen in fluid phase and such complexes are present in human serum and plasma. Importantly, while the presence of plasminogen did not affect the factor I cofactor activity of C4BP, the activation of plasminogen by urokinase-type plasminogen activator to active plasmin was significantly augmented in the presence of C4BP. Taken together, our data demonstrate a novel interaction between two proteins of the complement and fibrinolytic system. Most complexes might be formed during the acute phase of inflammation and have an effect on the homeostasis at the site of injury or acute inflammation. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
290
issue
30
pages
18333 - 18342
publisher
ASBMB
external identifiers
  • pmid:26067271
  • wos:000358512100007
  • scopus:84937773394
ISSN
1083-351X
DOI
10.1074/jbc.M114.619494
language
English
LU publication?
yes
id
5e16ff07-43f5-45d9-845f-f59dd79a1ea5 (old id 7486801)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26067271?dopt=Abstract
date added to LUP
2015-07-08 11:59:50
date last changed
2017-03-19 03:04:33
@article{5e16ff07-43f5-45d9-845f-f59dd79a1ea5,
  abstract     = {The complement, coagulation and fibrinolytic systems are crucial for the maintenance of tissue homeostasis. To date numerous interactions and cross talks have been identified between these cascades. In line with this, here we propose a novel, hitherto unknown interaction between the complement inhibitor C4b-binding protein (C4BP) and plasminogen of the fibrinolytic pathway. Binding of C4BP to S. pneumoniae is a known virulence mechanism of this pathogen and it was increased in the presence of plasminogen. Interestingly, the acute phase variant of C4BP lacking the β-chain and protein S binds plasminogen much stronger than the main isoform containing the β-chain and protein S. Indeed, the complement control protein (CCP) 8 domain of C4BP, which would otherwise be sterically hindered by the β-chain, primarily mediates this interaction. Moreover, the lysine-binding sites in plasminogen kringle domains facilitate the C4BP-plasminogen interaction. Furthermore, C4BP readily forms complexes with plasminogen in fluid phase and such complexes are present in human serum and plasma. Importantly, while the presence of plasminogen did not affect the factor I cofactor activity of C4BP, the activation of plasminogen by urokinase-type plasminogen activator to active plasmin was significantly augmented in the presence of C4BP. Taken together, our data demonstrate a novel interaction between two proteins of the complement and fibrinolytic system. Most complexes might be formed during the acute phase of inflammation and have an effect on the homeostasis at the site of injury or acute inflammation.},
  author       = {Agarwal, Vaibhav and Talens, Simone and Grandits, Alexander M and Blom, Anna},
  issn         = {1083-351X},
  language     = {eng},
  number       = {30},
  pages        = {18333--18342},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {A novel interaction between complement inhibitor C4b-binding protein and plasminogen that enhances plasminogen activation.},
  url          = {http://dx.doi.org/10.1074/jbc.M114.619494},
  volume       = {290},
  year         = {2015},
}