Presence of a Helix in Human CD4 Cytoplasmic Domain Promotes Binding to HIV-1 Nef Protein

Preußer, Andrea; Briese, Lars; Willbold, Dieter

doi:10.1006/bbrc.2002.6700

Cited by 16 publications

(16 citation statements)

References 49 publications

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“…Interestingly, the HIV-1 Nef protein binds to the same region of CD4 as FAK and with a similar affinity. 30 For this, Nef uses a binding surface that resembles the CD4 binding site of FAT (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for the Interaction between Focal Adhesion Kinase and CD4

Garron

Arthos

Guichou

et al. 2008

Journal of Molecular Biology

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Section: Discussionmentioning

confidence: 99%

Structural Basis for the Interaction between Focal Adhesion Kinase and CD4

Garron

Arthos

Guichou

et al. 2008

Journal of Molecular Biology

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“…Physical interaction of HIV-1 Nef and CD4 has been demon-strated in insect cells overexpressing both proteins (19), in yeast two-hybrid system (20) and in vitro binding assays using purified Nef protein and CD4 cytoplasmic domain peptides (21,59). In vitro binding of Nef to a CD4 C-tail peptide occurs via a hydrophobic patch on Nef including Trp-57, Leu-58, and Leu-110 residues and requires 2 leucines in the CD4 peptide (21).…”

Section: Discussionmentioning

confidence: 99%

CD4 Down-regulation by HIV-1 and Simian Immunodeficiency Virus (SIV) Nef Proteins Involves Both Internalization and Intracellular Retention Mechanisms

Rose

Janvier

Chandrasekhar

et al. 2005

Journal of Biological Chemistry

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Among the pleiotropic effects of Nef proteins of HIV and simian immunodeficiency virus (SIV), down-modulation of cell surface expression of CD4 is a prominent phenotype. It has been presumed that Nef proteins accelerate endocytosis of CD4 by linking the receptor to the AP-2 clathrin adaptor. However, the related AP-1 and AP-3 adaptors have also been shown to interact with Nef, hinting at role(s) for these complexes in the intracellular retention of CD4. By using genetic inhibitors of endocytosis and small interfering RNA-induced knockdown of AP-2, we show that accelerated CD4 endocytosis is not a dominant mechanism of HIV-1 (NL4-3 strain) Nef in epithelial cells, T lymphocyte cell lines, or peripheral blood lymphocytes. Furthermore, we show that both the CD4 recycling from the plasma membrane and the nascent CD4 in transit to the plasma membrane are susceptible to intracellular retention in HIV-1 Nefexpressing cells. In contrast, AP-2-mediated enhanced endocytosis constitutes the predominant mechanism for SIV (MAC-239 strain) Nef-induced down-regulation of human CD4 in human cells.

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“…On occasion, a small amount of fast antibody component (presumed free) was visible. (37,38) and in vivo in insect and mammalian cell expression systems expressing both proteins (39). Stable complexes between Nef-resistant LL/AA CD4 mutant and Nef have been demonstrated suggesting that the CD4 di-leucine may not be critical for Nef binding but may instead be needed to interact with the adapter complex (40).…”

Section: Differential Effects Of Sirna Knockdown Of Pacs-1 Arf6 Andmentioning

confidence: 99%

HIV-1 Nef Binds a Subpopulation of MHC-I throughout Its Trafficking Itinerary and Down-regulates MHC-I by Perturbing Both Anterograde and Retrograde Trafficking

Rosales

Rose

et al. 2010

Journal of Biological Chemistry

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The HIV protein Nef is thought to mediate immune evasion and promote viral persistence in part by down-regulating major histocompatibility complex class I protein (MHC-I or HLA-I) from the cell surface. Two different models have been proposed to explain this phenomenon as follows: 1) stimulation of MHC-I retrograde trafficking from and aberrant recycling to the plasma membrane, and 2) inhibition of anterograde trafficking of newly synthesized HLA-I from the endoplasmic reticulum to the plasma membrane. We show here that Nef simultaneously uses both mechanisms to down-regulate HLA-I in peripheral blood mononuclear cells or HeLa cells. Consistent with this, we found by using fluorescence correlation spectroscopy that a third of diffusing HLA-I at the endoplasmic reticulum, Golgi/transGolgi network, and the plasma membrane (PM) was associated with Nef. The binding of Nef was similarly avid for native HLA-I and recombinant HLA-I A2 at the PM. Nef binding to HLA-I at the PM was sensitive to specific inhibition of endocytosis. It was also attenuated by cyclodextrin disruption of PM lipid microdomain architecture, a change that also retarded lateral diffusion and induced large clusters of HLA-I. In all, our data support a model for Nef down-regulation of HLA-I that involves both major trafficking itineraries and persistent protein-protein interactions throughout the cell.

show abstract

Presence of a Helix in Human CD4 Cytoplasmic Domain Promotes Binding to HIV-1 Nef Protein

Cited by 16 publications

References 49 publications

Structural Basis for the Interaction between Focal Adhesion Kinase and CD4

Structural Basis for the Interaction between Focal Adhesion Kinase and CD4

CD4 Down-regulation by HIV-1 and Simian Immunodeficiency Virus (SIV) Nef Proteins Involves Both Internalization and Intracellular Retention Mechanisms

HIV-1 Nef Binds a Subpopulation of MHC-I throughout Its Trafficking Itinerary and Down-regulates MHC-I by Perturbing Both Anterograde and Retrograde Trafficking

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