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Functional Role of C-Terminal Sequence Elements in the Transporter Associated with Antigen Processing¹

Sarah Ehses^*, Ralf M. Leonhardt^*, Guido Hansen and Michael R. Knittler^2,*

^* Institute for Genetics and Institute of Biochemistry, University of Cologne, Cologne, Germany

TAP delivers antigenic peptides into the endoplasmic reticulum (ER) that are subsequently bound by MHC class I molecules. TAP consists of two subunits (TAP1 and TAP2), each with a transmembrane (TMD) and a nucleotide-binding (NBD) domain. The two TAP-NBDs have distinct biochemical properties and control different steps during the peptide translocation process. We noted previously that the nonhomologous C-terminal tails of rat TAP1 and TAP2 determine the distinct functions of TAP-NBD1 and -NBD2. To identify the sequence elements responsible for the asymmetrical NBD function, we constructed chimeric rat TAP variants in which we systematically exchanged sequence regions of different length between the two TAP-NBDs. Our fine-mapping studies demonstrate that a nonhomologous region containing the 6/10-loop in conjunction with the downstream switch region is directly responsible for the functional separation of the TAP-NBDs. The 6/10-loop determines the nonsynonymous nucleotide binding of NBD1 and NBD2, whereas the switch region seems to play a critical role in regulating the functional cross-talk between the structural domains of TAP. Based on our findings, we postulate that these two sequence elements build a minimal functional unit that controls the asymmetry of the two TAP-NBDs.

This article has been cited by other articles:

				K. Keusekotten, R. M. Leonhardt, S. Ehses, and M. R. Knittler Biogenesis of Functional Antigenic Peptide Transporter TAP Requires Assembly of Pre-existing TAP1 with Newly Synthesized TAP2 J. Biol. Chem., June 30, 2006; 281(26): 17545 - 17551. [Abstract] [Full Text] [PDF]