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J. Biol. Chem., Vol. 281, Issue 32, 22827-22838, August 11, 2006

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The Single Ligand-binding Repeat of Tva, a Low Density Lipoprotein Receptor-related Protein, Contains Two Ligand-binding Surfaces^*

From the Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908-0732

The receptor for avian sarcoma/leukosis virus subtype A (ASLV-A), Tva, is the simplest member of the low density lipoprotein receptor family containing a single ligand-binding repeat (LBR). Most LBRs contain a central Trp (Trp³³ in Tva) that is important for ligand binding and, for the low density lipoprotein receptor, is associated with familial hypercholesterolemia. The Tva ligand-binding module contains a second Trp (Trp⁴⁸) that is part of a DEW motif present in a subset of LBRs. Trp⁴⁸ is important for ASLV-A infectivity. A soluble Tva (sTva) ligand-binding module is sufficient for ASLV-A infectivity. Tva interacts with the viral glycoprotein, and a soluble receptor-binding domain (SUA) binds sTva with picomolar affinity. We investigated whether Tva, a retroviral receptor, could behave as a classic LBR by assessing sTva interactions with the universal receptor-associated protein (RAP) and comparing these interactions with those between sTva and its viral ligand (SUA). To address the role of the two Trp residues in Tva function, we prepared sTva harboring mutations of Trp³³, Trp⁴⁸, or both and determined the binding kinetics with RAP and SUA. We found that sTva behaved as a "normal" receptor toward RAP, requiring both calcium and Trp³³ for binding. However, sTva binding to SUA required neither calcium nor Trp³³. Furthermore, sTva could bind both RAP and SUA simultaneously. These results show that the single LBR of Tva has two ligand-binding sites, raising the possibility that other LBRs may also.

Received for publication, November 28, 2005 , and in revised form, May 16, 2006.

^* This work was supported by Grant 0365322U from the American Heart Association, Mid-Atlantic Division (to S. E. D.), and by Grant AI22470 from the National Institutes of Health (to Dr. Judith M. White). 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, School of Medicine, University of Virginia, P. O. Box 800732, Charlottesville, VA 22908-0732. Tel.: 434-924-2009; Fax: 434-982-3912; E-mail: sed7a{at}virginia.edu.

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