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

Molecular Immunology
Marcin OkrojA M Blom

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 ...Continue Reading

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Citations

May 3, 2011·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Xu-Wei CaiFeng-Ming Spring Kong
Dec 15, 2015·Immunology Letters·David Ermert, Anna M Blom
Jan 16, 2009·Trends in Immunology·A P SjöbergA M Blom
Jun 1, 2010·International Journal of Radiation Oncology, Biology, Physics·Xu-Wei CaiFeng-Ming Spring Kong

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