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* Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Institute of Immunology, Tuebingen, Germany; and
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
Tapasin organizes the peptide-loading complex (PLC) by recruiting peptide-receptive MHC class I (MHC-I) and accessory chaperones to the N-terminal regions of the TAP subunits TAP1 and TAP2. Despite numerous studies have shown that the formation of the PLC is essential to facilitate proper MHC-I loading, the molecular architecture of this complex is still highly controversial. We studied the stoichiometry of the PLC by blue native-PAGE in combination with Ab-shift assays and found that TAP/tapasin complexes exist at steady state as a mixture of two distinct oligomers of 350 and 450 kDa. Only the higher m.w. complex contains MHC-I and disulfide-linked tapasin/ER60 conjugates. Moreover, we show for the first time to our knowledge that the fully assembled PLC comprises two tapasin, two ER60, but only one complex of MHC-I and calreticulin. Based hereon we postulate that the TAP subunits alternate in the recruitment and loading of a single MHC-I.
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.
1 This work was supported by financial assistance provided by the Friedrich-Loeffler-Institute and Grant KN541-1 from the Deutsche Forschungsgemeinschaft.
2 E.R. and R.M.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Michael R. Knittler, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Institute of Immunology, Paul-Ehrlich-Strasse 28, D-72076 Tuebingen, Germany. E-mail address: michael.knittler{at}fli.bund.de
4 Abbreviations used in this paper: TAP, transporter associated with antigen processing; ER, endoplasmic reticulum; PLC, peptide-loading complex; NEM, N-ethylmaleimide; PDI, protein disulfide isomerase; BN, blue native.
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