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J. Biol. Chem., Vol. 283, Issue 6, 3011-3022, February 8, 2008

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The Tyrosine Binding Pocket in the Adaptor Protein 1 (AP-1) µ1 Subunit Is Necessary for Nef to Recruit AP-1 to the Major Histocompatibility Complex Class I Cytoplasmic Tail^*

Elizabeth R. Wonderlich¹, Maya Williams¹², and Kathleen L. Collins^¶3

From the Cellular and Molecular Biology Graduate Program, Department of Microbiology and Immunology, and ^¶Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109

To evade the anti-human immunodeficiency virus (HIV) immune response, the HIV Nef protein disrupts major histocompatibility complex class I (MHC-I) trafficking by recruiting the clathrin adaptor protein 1 (AP-1) to the MHC-I cytoplasmic tail. Under normal conditions AP-1 binds dileucine and tyrosine signals (YXX motifs) via physically separate binding sites. In the case of the Nef-MHC-I complex, a tyrosine in the human leukocyte antigen (HLA)-A2 cytoplasmic tail (³²⁰YSQA) and a methionine in Nef (Met²⁰) are absolutely required for AP-1 binding. Also present in Nef is a dileucine motif, which does not normally affect MHC-I trafficking and is not needed to recruit AP-1 to the Nef-MHC-I-complex. However, evidence is presented here that this dileucine motif can be activated by fusing Nef to the HLA-A2 tail in cis. Thus, the inability of this motif to function in trans likely results from a structural change that occurs when Nef binds to the MHC-I cytoplasmic tail. The physiologically relevant tyrosine-dependent recruitment of AP-1 to MHC-I, which occurs whether Nef is present in cis or trans, was stabilized by the acidic and polyproline domains within Nef. Additionally, amino acids Ala³²⁴ and Asp³²⁷ in the cytoplasmic tails of HLA-A and (but not HLA-C and HLA-E) molecules also stabilized AP-1 binding. Finally, mutation of the tyrosine binding pocket in the µ subunit of AP-1 created a dominant negative inhibitor of Nef-induced down-modulation of HLA-A2 that disrupted binding of wild type AP-1 to the Nef-MHC-I complex. Thus, these data provide evidence that Nef binding to the MHC-I cytoplasmic tail stabilizes the interaction of a tyrosine in the MHC-I cytoplasmic tail with the natural tyrosine binding pocket in AP-1.

Received for publication, September 17, 2007 , and in revised form, November 30, 2007.

^* This research was supported by National Institutes of Health Grant RO1AI46998 and University of Michigan Biological Scholars Program. 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 Table 1.

¹ Supported by the University of Michigan Cellular and Molecular Biology Training Program.

² Supported by the Microbial Pathogenesis Training Program and a University of Michigan Rackham Merit Fellowship.

³ To whom correspondence should be addressed: Dept. of Internal Medicine, 3510 MSRB I Box 0652, 1150 West Medical Center Dr., The University of Michigan, Ann Arbor, MI 48109-0652. Tel.: 734-615-1320; Fax: 734-615-5252; E-mail: klcollin{at}umich.edu.

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