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J. Biol. Chem., Vol. 279, Issue 50, 52552-52557, December 10, 2004

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Interaction of Calcium-bound C-reactive Protein with Fibronectin Is Controlled by pH

IN VIVO IMPLICATIONS^*

Madathilparambil V. Suresh, Sanjay K. Singh, and Alok Agrawal

From the Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614

C-reactive protein (CRP) binds with high affinity to fibronectin (Fn), a major component of the extracellular matrix (ECM), but at physiological pH the binding is inhibited by calcium ions (Ca²⁺). Because CRP circulates in the blood in Ca²⁺-bound form, the occurrence of CRP-Fn interactions in vivo has been doubtful. To define the basis of inhibition of CRP-Fn interaction by Ca²⁺ at pH 7.0, we hypothesized that Fn-binding site on CRP consisted of amino acids co-ordinating Ca²⁺. Site-directed mutagenesis of amino acids co-ordinating Ca²⁺ drastically decreased the binding of CRP to Fn, indicating that the Ca²⁺-binding site indeed formed the Fn-binding site. To determine the requirements for possible interaction between Ca²⁺-bound CRP and Fn, we investigated inhibition of CRP-Fn interaction by Ca²⁺ as a function of pH. Ca²⁺ did not inhibit binding of CRP to Fn at pH 6.5 and lower. The contrasting Fn binding properties of CRP at physiological and mildly acidic pH indicated that the interaction of Ca²⁺-bound CRP with Fn was controlled by pH. We conclude that the inhibition of binding of CRP to Fn by Ca²⁺ at pH 7.0 is a mechanism to prevent CRP-Fn interactions under normal conditions. CRP, in its Ca²⁺-bound state, is capable of binding Fn but only at the inflammatory sites and tumors with low pH. CRP, Fn, and the ECM all have been implicated in cancer. Taken together our data raise the possibility that CRP-Fn interactions may change the architecture of ECM to modify the development of tumors.

Received for publication, August 9, 2004 , and in revised form, September 20, 2004.

^* This work was supported by National Institutes of Health Grant HL071233. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, P. O. Box 70577, Johnson City, TN 37614. Tel.: 423-439-6336; Fax: 423-439-8773; E-mail: agrawal{at}etsu.edu.

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