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Journal of Virology, February 2008, p. 1166-1174, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01874-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Diacidic Motif in Human Immunodeficiency Virus Type 1 Nef Is a Novel Determinant of Binding to AP-2{triangledown}

O. Wolf Lindwasser,1 William J. Smith,1 Rittik Chaudhuri,1 Peter Yang,1 James H. Hurley,2 and Juan S. Bonifacino1*

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development,1 Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 27 August 2007/ Accepted 6 November 2007

A key function of the Nef protein of immunodeficiency viruses is the downregulation of the T-cell and macrophage coreceptor, CD4, from the surfaces of infected cells. CD4 downregulation depends on a conserved (D/E)XXXL(L/I)-type dileucine motif in the C-terminal, flexible loop of Nef, which mediates binding to the clathrin adaptor complexes AP-1, AP-2, and AP-3. We now report the identification of a consensus (D/E)D motif within this loop as a second, conserved determinant of interaction of Nef with AP-2, though not with AP-1 and AP-3. Mutations in this diacidic motif abrogate both AP-2 binding and CD4 downregulation. We also show that a dileucine motif from tyrosinase, both in its native context and in the context of Nef, can bind to AP-2 independently of a diacidic motif. These results thus identify a novel type of AP-2 interaction determinant, support the notion that AP-2 is the key clathrin adaptor for the downregulation of CD4 by Nef, and reveal a previously unrecognized diversity among dileucine sorting signals.

* Corresponding author. Mailing address: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T, Room 101, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-6368. Fax: (301) 402-0078. E-mail: juan{at}helix.nih.gov

{triangledown} Published ahead of print on 21 November 2007.

Journal of Virology, February 2008, p. 1166-1174, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01874-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Laguette, N., Bregnard, C., Bouchet, J., Benmerah, A., Benichou, S., Basmaciogullari, S. (2009). Nef-Induced CD4 Endocytosis in Human Immunodeficiency Virus Type 1 Host Cells: Role of p56lck Kinase. J. Virol. 83: 7117-7128 [Abstract] [Full Text]  
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