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J. Biol. Chem., Vol. 280, Issue 47, 39143-39151, November 25, 2005

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Domain Unfolding Plays a Role in Superfibronectin Formation^*

From the Department of Cell Biology, Duke University, Medical Center, Durham, North Carolina 27710

Superfibronectin (sFN) is a fibronectin (FN) aggregate that is formed by mixing FN with anastellin, a fragment of the first type III domain of FN. However, the mechanism of this aggregation has not been clear. In this study, we found that anastellin co-precipitated with FN in a ratio of 4:1, anastellin:FN monomer. The primary binding site for anastellin was in the segment ^III1–3, which bound three molecules of anastellin and was able to form a precipitate without the rest of the FN molecule. Anastellin binding to ^III3 caused a conformational change in that domain that exposed a cryptic thermolysin-sensitive site. An additional anastellin binds to ^III11, where it enhances thermolysin digestion of ^III11. An engineered disulfide bond in ^III3 inhibited both aggregation and protease digestion, suggesting that the stability of ^III3 is a key factor in sFN formation. We propose a three-step model for sFN formation: 1) FN-III domains spontaneously unfold and refold; 2) anastellin binds to an unfolded domain, preventing its refolding and leaving it with exposed hydrophobic surfaces and -sheet edges; and 3) these exposed elements bind to similar exposed elements on other molecules, leading to aggregation. The model is consistent with our observation that the kinetics of aggregation are first order, with a reaction time of 500–700 s. Similar mechanisms may contribute to the assembly of the native FN matrix.

Received for publication, August 17, 2005 , and in revised form, September 27, 2005.

^* This work was supported by National Institutes of Health Grant CA47056. 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.

¹ To whom correspondence should be addressed: Dept. of Cell Biology, Box 3709, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-6385; Fax: 919-684-8090; E-mail: H.Erickson{at}cellbio.duke.edu.

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