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The human cytomegalovirus gene product US6 inhibits ATP binding by TAP
Author(s) -
Hewitt Eric W.,
Gupta Soma Sen,
Lehner Paul J.
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.3.387
Subject(s) - biology , transporter associated with antigen processing , endoplasmic reticulum , major histocompatibility complex , mhc class i , gene product , binding site , antigen presentation , microbiology and biotechnology , antigen processing , plasma protein binding , biochemistry , gene , cytotoxic t cell , gene expression , in vitro
Human cytomegalovirus (HCMV) encodes several genes that disrupt the major histocompatibility complex (MHC) class I antigen presentation pathway. We recently described the HCMV‐encoded US6 gene product, a 23 kDa endoplasmic reticulum (ER)‐resident type I integral membrane protein that binds to the transporter associated with antigen processing (TAP), inhibits peptide translocation and prevents MHC class I assembly. The functional consequence of this inhibition is to prevent the cell surface expression of class I bound viral peptides and their recognition by HCMV‐specific cytotoxic T cells. Here we describe a novel mechanism of action for US6. We demonstrate that US6 inhibits the binding of ATP by TAP1. This is a conformational effect, as the ER lumenal domain of US6 is sufficient to inhibit ATP binding by the cytosolic nucleotide binding domain of TAP1. US6 also stabilizes TAP at 37°C and prevents conformational rearrangements induced by peptide binding. Our findings suggest that the association of US6 with TAP stabilizes a conformation in TAP1 that prevents ATP binding and subsequent peptide translocation.