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Journal of Virology, February 2008, p. 1249-1258, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.00660-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cooperative Binding of the Class I Major Histocompatibility Complex Cytoplasmic Domain and Human Immunodeficiency Virus Type 1 Nef to the Endosomal AP-1 Complex via Its µ Subunit{triangledown}

Colleen M. Noviello,1 Serge Benichou,2,3 and John C. Guatelli1,4*

Department of Medicine, University of California—San Diego, California 92093-0679,1 Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, France,2 Inserm U567, Paris, France,3 San Diego Veterans Affairs Healthcare System, San Diego, California4

Received 28 March 2007/ Accepted 19 November 2007

Human immunodeficiency virus type 1 Nef provides immune evasion by decreasing the expression of major histocompatibility complex class I (MHC-I) at the surfaces of infected cells. The endosomal clathrin adaptor protein complex AP-1 is a key cellular cofactor for this activity, and it is recruited to the MHC-I cytoplasmic domain (CD) in the presence of Nef by an uncharacterized mechanism. To determine the molecular basis of this recruitment, we used an MHC-I CD-Nef fusion protein to represent the MHC-I CD/Nef complex during protein interaction assays. The MHC-I CD had no intrinsic ability to bind AP-1, but it conferred binding activity when fused to Nef. This activity was independent of the canonical leucine-based AP-binding motif in Nef; it required residue Y320 in the MHC-I CD and residues E62-65 and P78 in Nef, and it involved the µ but not the {gamma}/{sigma} subunits of AP-1. The impaired binding of mutants encoding substitutions of E62-65 or P78 in Nef was rescued by replacing the Y320SQA sequence in the MHC-I CD with YSQL, suggesting that Nef allows the YSQA sequence to act as if it were a canonical µ-binding motif. These data identify the µ subunit of AP-1 (µ1) as the key target of the MHC-I CD/Nef complex, and they indicate that both Y320 in the MHC-I CD and E62-65 in Nef interact directly with µ1. The data support a cooperative binding model in which Nef functions as a clathrin-associated sorting protein that allows recognition of an incomplete, tyrosine-based µ-binding signal in the MHC-I CD by AP-1.

* Corresponding author. Mailing address: University of California—San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0679. Phone: (858) 552-7439. Fax: (858) 552-7445. E-mail: jguatelli{at}ucsd.edu

{triangledown} Published ahead of print on 5 December 2007.

Journal of Virology, February 2008, p. 1249-1258, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.00660-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chaudhuri, R., Mattera, R., Lindwasser, O. W., Robinson, M. S., Bonifacino, J. S. (2009). A Basic Patch on {alpha}-Adaptin Is Required for Binding of Human Immunodeficiency Virus Type 1 Nef and Cooperative Assembly of a CD4-Nef-AP-2 Complex. J. Virol. 83: 2518-2530 [Abstract] [Full Text]  
  • Baugh, L. L., Garcia, J. V., Foster, J. L. (2008). Functional Characterization of the Human Immunodeficiency Virus Type 1 Nef Acidic Domain. J. Virol. 82: 9657-9667 [Abstract] [Full Text]  


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