TY - JOUR TI - How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4 AU - Ren, Xuefeng AU - Park, Sang Yoon AU - Bonifacino, Juan S AU - Hurley, James H A2 - Sundquist, Wesley VL - 3 PY - 2014 DA - 2014/01/28 SP - e01754 C1 - eLife 2014;3:e01754 DO - 10.7554/eLife.01754 UR - https://doi.org/10.7554/eLife.01754 AB - 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. KW - HIV-1 KW - protein crystallography KW - membrane traffic JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -