STRUCTURE AND FUNCTION OF PEPTIDE TRANSPORTERS

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CD8+ T cells (TCD8+) play an important role in controlling virus infections. TCD8+ recognize peptides of 8 to 10 residues derived from viral proteins located in the cytosol of virus infected cells. These peptides are recognized in a complex with class I molecules encoded by the major histocompatibility complex (MHC). In the past 4 years it was discovered that the MHC also encodes two molecules, termed TAP1 and TAP2, that combine in a 1:1 ratio to create a complex that specifically transports peptides from the cytosol into the endoplasmic reticulum (ER). Human TAP genes display at least some limited polymorphism. The existence of these peptide pumps and their polymorphism raises a number of important questions: Where in the cells are the pumps located? Do the pumps influence the types of peptides presented by class I molecules? Are the pumps tethered to the proteases that produce antigenic peptides in the cytosol? How do the pumps work? Are there individuals with immune deficiencies based on mutations in the TAP genes? Can cells transport peptides via other mechanisms? To help characterize the structure and function of the TAP genes we have created recombinant vaccinia viruses (rVV) that express either TAP1 (VV-TAP1/h), TAP2 (VV- TAP2/h), or TAP1 and TAP2 (VV-TAP[1&2]/h) and are in the process of creating an equivalent set of rVVs expressing mouse TAP. We have demonstrated that each of rVVs express functional subunits, or in the case of the VV-TAP[1&2]/h, a functional transporter. Using this panel of rVVs we have studied the assembly, intracellular location, and biochemical properties of TAP1 and TAP2, and in collaboration with other laboratories, demonstrated that a Herpes virus protein binds human TAP and blocks its function. We have also begun to examine the ability of an homologous protein associated with multiple drug resistance of tumor cells (MDR) to transport cytosolic peptides for binding to class I molecules.