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J. Biol. Chem., Vol. 279, Issue 11, 10142-10147, March 12, 2004

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Functional Dissection of the Transmembrane Domains of the Transporter Associated with Antigen Processing (TAP)^*

Joachim Koch, Renate Guntrum, Susanne Heintke, Christoph Kyritsis, and Robert Tampé

From the Institute of Biochemistry, Biocenter, Johann Wolfgang Goethe-University Frankfurt, Marie-Curie Strasse 9, D-69439 Frankfurt, Germany

The transporter associated with antigen processing (TAP1/2) translocates cytosolic peptides of proteasomal degradation into the endoplasmic reticulum (ER) lumen. A peptide-loading complex of tapasin, major histocompatibility complex class I, and several auxiliary factors is assembled at the transporter to optimize antigen display to cytotoxic T-lymphocytes at the cell surface. The heterodimeric TAP complex has unique N-terminal domains in addition to a 6 + 6-transmembrane segment core common to most ABC transporters. Here we provide direct evidence that this core TAP complex is sufficient for (i) ER targeting, (ii) heterodimeric assembly within the ER membrane, (iii) peptide binding, (iv) peptide transport, and (v) specific inhibition by the herpes simplex virus protein ICP47 and the human cytomegalovirus protein US6. We show for the first time that the translocation pore of the transporter is composed of the predicted TM-(5–10) of TAP1 and TM-(4–9) of TAP2. Moreover, we demonstrate that the N-terminal domains of TAP1 and TAP2 are essential for recruitment of tapasin, consequently mediating assembly of the macromolecular peptide-loading complex.

Received for publication, November 24, 2003 , and in revised form, December 12, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 628-Functional Membrane Proteomics. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 49-69-798-29475; Fax: 49-69-798-29495; E-mail: tampe{at}em.uni-frankfurt.de.

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