How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4.
The Nef protein of HIV-1 downregulates the cell surface co-receptor CD4 by hijacking the clathrin adaptor complex AP-2. The structural basis for the hijacking of AP-2 by Nef is revealed by a 2.9 Å crystal structure of Nef bound to the α and σ2 subunits of AP-2. Nef binds to AP-2 via its central loop (residues 149-179) and its core. The determinants for Nef binding include residues that directly contact AP-2 and others that stabilize the binding-competent conformation of the central loop. Residues involved in both direct and indirect interactions are required for the binding of Nef to AP-2 and for downregulation of CD4. These results lead to a model for the docking of the full AP-2 tetramer to membranes as bound to Nef, such that the cytosolic tail of CD4 is situated to interact with its binding site on Nef. DOI: http://dx.doi.org/10.7554/eLife.01754.001.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
Xuefeng
X
Ren
Sang Yoon
SY
Park
Juan S
JS
Bonifacino
James H
JH
Hurley
D033962:Adaptor Protein Complex 2 / Q000737:chemistry / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D018360:Crystallography, X-Ray; D015536:Down-Regulation; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
D033962:Adaptor Protein Complex 2; D015704:CD4 Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
HIV-1; membrane traffic; protein crystallography