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J. Biol. Chem., Vol. 281, Issue 25, 17259-17265, June 23, 2006

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A Zinc-binding Region in Vif Binds Cul5 and Determines Cullin Selection^*

Andrew Mehle¹, Elaine R. Thomas, Kottampatty S. Rajendran, and Dana Gabuzda^¶2

From the Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, Massachusetts 02115, and Departments of Pathology and ^¶Neurology, Harvard Medical School, Boston, Massachusetts 02115

Human immunodeficiency virus-1 (HIV-1) Vif overcomes the anti-viral activity of APOBEC3G by targeting it for ubiquitination via a Cullin 5-ElonginB-ElonginC (Cul5-EloBC) E3 ligase. Vif associates with Cul5-EloBC through a BC-box motif that binds EloC, but the mechanism by which Vif selectively recruits Cul5 is poorly understood. Here we report that a region of Vif (residues 100-142) upstream of the BC-box binds selectively to Cul5 in the absence of EloC. This region contains a zinc coordination site HX₅CX_17-18CX_3-5H (HCCH), with His/Cys residues at positions 108, 114, 133, and 139 coordinating one zinc ion. The HCCH zinc coordination site, which is conserved among primate lentivirus Vif proteins, does not correspond to any known class of zinc-binding motif. Mutations of His/Cys residues in the HCCH motif impair zinc coordination, Cul5 binding, and APOBEC3G degradation. Mutations of conserved hydrophobic residues (Ile-120, Ala-123, and Leu-124) located between the two Cys residues in the HCCH motif disrupt binding of the zinc-coordinating region to Cul5 and inhibit APOBEC3G degradation. The Vif binding site maps to the first cullin repeat in the N terminus of Cul5. These data suggest that the zinc-binding region in Vif is a novel cullin interaction domain that mediates selective binding to Cul5. We propose that the HCCH zinc-binding motif facilitates Vif-Cul5 binding by playing a structural role in positioning hydrophobic residues for direct contact with Cul5.

Received for publication, March 15, 2006 , and in revised form, April 24, 2006.

^* This work was supported by National Institutes of Health Grants AI36186 and AI62555. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ Supported in part by a National Science Foundation predoctoral fellowship.

² To whom correspondence should be addressed: Dana-Farber Cancer Inst., JF816, 44 Binney St., Boston, MA 02115. Tel.: 617-632-2154; Fax: 617-632-3113; E-mail: dana_gabuzda{at}dfci.harvard.edu.

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