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Structural basis and functional effects of the interaction between complement inhibitor C4b-binding protein and DNA.

Okroj, Marcin LU ; Jenkins, Huw T; Herbert, Andrew P; Barlow, Paul N and Blom, Anna M (2008) In Molecular Immunology 46. p.62-69
Abstract
Human C4b-binding protein (C4BP) is a soluble, multiple-subunit inhibitor of complement that circulates in blood. Recently C4BP was shown to bind DNA, reduce DNA release from necrotic cells and limit DNA-mediated complement activation in solution. Herein we employed nuclear magnetic resonance spectroscopy to measure chemical shift perturbations and used them to restrain the computational docking of a B-form 10-base-pair DNA molecule onto the solution structure of C4BP alpha-chain complement control protein (CCP) domains 1-2 (C4BP12). Six amino acid residues located on one face of the interdomain junction - Val(38), Ser(40), Thr(43), Tyr(62), Lys(63) and Arg(64) - exhibited the largest chemical shift changes. In the model, the DNA lies in a... (More)
Human C4b-binding protein (C4BP) is a soluble, multiple-subunit inhibitor of complement that circulates in blood. Recently C4BP was shown to bind DNA, reduce DNA release from necrotic cells and limit DNA-mediated complement activation in solution. Herein we employed nuclear magnetic resonance spectroscopy to measure chemical shift perturbations and used them to restrain the computational docking of a B-form 10-base-pair DNA molecule onto the solution structure of C4BP alpha-chain complement control protein (CCP) domains 1-2 (C4BP12). Six amino acid residues located on one face of the interdomain junction - Val(38), Ser(40), Thr(43), Tyr(62), Lys(63) and Arg(64) - exhibited the largest chemical shift changes. In the model, the DNA lies in a cleft formed by the interdomain interface. The double-helix is perpendicular to the long axis of C4BP12 consistent with the multiple arms of C4BP binding to adjacent sites on a longer DNA molecule. The DNA lies in a region previously shown to bind C4b and heparin and these molecules (but not C3b) inhibited the DNA-C4BP interaction. Nonetheless, crucial C4BP functions such as cofactor activity for factor I cleavage of C4b and C3b, and decay acceleration of the classical C3 convertase appeared not to be affected by the presence of DNA. Taken together these results reinforce the case for the occupation of some of the seven arms of C4BP in a multivalent interaction with DNA or surface bound glycosaminoglycans while other arms engage C4b or C3b. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Immunology
volume
46
pages
62 - 69
publisher
Pergamon
external identifiers
  • wos:000260807700007
  • pmid:18715646
  • scopus:52949106501
ISSN
1872-9142
DOI
10.1016/j.molimm.2008.07.008
language
English
LU publication?
yes
id
b788cdcb-9f5a-4c51-80b8-5c6abff250f1 (old id 1223040)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18715646?dopt=Abstract
date added to LUP
2008-09-03 13:10:06
date last changed
2017-01-01 07:51:32
@article{b788cdcb-9f5a-4c51-80b8-5c6abff250f1,
  abstract     = {Human C4b-binding protein (C4BP) is a soluble, multiple-subunit inhibitor of complement that circulates in blood. Recently C4BP was shown to bind DNA, reduce DNA release from necrotic cells and limit DNA-mediated complement activation in solution. Herein we employed nuclear magnetic resonance spectroscopy to measure chemical shift perturbations and used them to restrain the computational docking of a B-form 10-base-pair DNA molecule onto the solution structure of C4BP alpha-chain complement control protein (CCP) domains 1-2 (C4BP12). Six amino acid residues located on one face of the interdomain junction - Val(38), Ser(40), Thr(43), Tyr(62), Lys(63) and Arg(64) - exhibited the largest chemical shift changes. In the model, the DNA lies in a cleft formed by the interdomain interface. The double-helix is perpendicular to the long axis of C4BP12 consistent with the multiple arms of C4BP binding to adjacent sites on a longer DNA molecule. The DNA lies in a region previously shown to bind C4b and heparin and these molecules (but not C3b) inhibited the DNA-C4BP interaction. Nonetheless, crucial C4BP functions such as cofactor activity for factor I cleavage of C4b and C3b, and decay acceleration of the classical C3 convertase appeared not to be affected by the presence of DNA. Taken together these results reinforce the case for the occupation of some of the seven arms of C4BP in a multivalent interaction with DNA or surface bound glycosaminoglycans while other arms engage C4b or C3b.},
  author       = {Okroj, Marcin and Jenkins, Huw T and Herbert, Andrew P and Barlow, Paul N and Blom, Anna M},
  issn         = {1872-9142},
  language     = {eng},
  pages        = {62--69},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {Structural basis and functional effects of the interaction between complement inhibitor C4b-binding protein and DNA.},
  url          = {http://dx.doi.org/10.1016/j.molimm.2008.07.008},
  volume       = {46},
  year         = {2008},
}