A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4

Greenberg, M., DeTulleo, L., Rapoport, I., Skowronski, J., Kirchhausen, T. (1998) A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4. Current Biology, 8 (22). pp. 1239-42. ISSN 0960-9822

URL: http://www.ncbi.nlm.nih.gov/pubmed/9811611
DOI: 10.1016/S0960-9822(07)00518-0

Abstract

Nef, a approximately 200 residue multifunctional regulatory protein of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), interacts with components of host cell signal transduction and clathrin-dependent protein sorting pathways. The downregulation of surface CD4 molecules and major histocompatibility complex (MHC) class I antigens by Nef is believed to be important in AIDS pathogenesis [1-7]. Nef contains a globular core domain and two disordered segments--a myristylated arm at the amino terminus and a carboxy-terminal loop projecting from the globular core [8,9]. Here, we aimed to determine the sorting signals in HIV-1 Nef that were responsible for its involvement in the clathrin-mediated pathway. We found that a sequence in the carboxy-terminal disordered loop of Nef is essential for downregulation of CD4. This sequence resembles the dileucine motif, one of two well-characterized sorting signals that target membrane proteins to clathrin-coated vesicles. The dileucine-motif-containing segment of Nef bound directly and specifically to the beta-adaptin subunit of the clathrin adaptor complexes AP-1 and AP-2, which are responsible for recruiting sorted proteins into coated pits. Unlike wild-type Nef, a mutant form of Nef that lacked the dileucine motif did not localize to clathrin-coated pits and did not downregulate CD4 expression, although it could downregulate MHC class I surface expression. Thus, the dileucine motif in HIV-1 is required for CD4 downregulation and for interaction with clathrin adaptor complexes.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Sequence Antigens, CD4/ metabolism Clathrin/ metabolism Coated Pits, Cell-Membrane/ metabolism Down-Regulation Gene Products, nef/genetics/ metabolism HIV-1/ metabolism Humans Leucine/ metabolism Molecular Sequence Data Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.
Subjects: bioinformatics > genomics and proteomics > design > amino acid design
diseases & disorders > viral diseases > HIV
diseases & disorders > viral diseases > SIV
organs, tissues, organelles, cell types and functions > organs types and functions > metabolism
CSHL Authors:
Communities: CSHL labs > Skowronski lab
Depositing User: Kathleen Darby
Date Deposited: 01 May 2014 19:52
Last Modified: 01 May 2014 19:52
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29885

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