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Journal of Virology, March 2006, p. 3050-3061, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.3050-3061.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Hydrophobic Binding Surface on the Human Immunodeficiency Virus Type 1 Nef Core Is Critical for Association with p21-Activated Kinase 2

Kristin Agopian,1 Bangdong L. Wei,3 J. Victor Garcia,3 and Dana Gabuzda1,2*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,1 Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115,2 Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 753903

Received 18 August 2005/ Accepted 20 December 2005

The interaction of human immunodeficiency virus type 1 (HIV-1) Nef with p21-activated kinase 2 (Pak2) has been proposed to play an important role in T-cell activation and disease progression during viral infection. However, the mechanism by which Nef activates Pak2 is poorly understood. Mutations in most Nef motifs previously reported to be required for Pak2 activation (G2, PxxP72, and RR105) also affect other Nef functions, such as CD4 or major histocompatibility complex class I (MHC-I) downregulation. To better understand Nef interactions with Pak2, we performed mutational analysis of three primary HIV-1 Nef clones that exhibited similar capacities for downregulation of CD4 and MHC-I but variable abilities to associate with activated Pak2. Our results demonstrate that Nef amino acids at positions 85, 89, 187, 188, and 191 (L, H, S, R, and F in the clade B consensus, respectively) are critical for Pak2 association. Mutation of these Nef residues dramatically altered association with Pak2 without affecting Nef expression levels or CD4 and MHC-I downregulation. Furthermore, compensation occurred at positions 89 and 191 when both amino acids were substituted. Since residues 85, 89, 187, 188, and 191 cluster on the surface of the Nef core domain in a region distinct from the dimerization and SH3-binding domains, we propose that these Nef residues form part of a unique binding surface specifically involved in association with Pak2. This binding surface includes exposed and recessed hydrophobic residues and may participate in an as-yet-unidentified protein-protein interaction to facilitate Pak2 activation.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, JFB 816, 44 Binney St., Boston, MA 02115. Phone: (617) 632-2154. Fax: (617) 632-3113. E-mail: dana_gabuzda{at}dfci.harvard.edu.

Journal of Virology, March 2006, p. 3050-3061, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.3050-3061.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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