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* Institut für Immunologie, Johannes-Gutenberg-Universität Mainz, Mainz;
Institut für Zellbiologie/Immunologie, Universität Tübingen, Tübingen;
Institut für Biochemie, Charité, Humboldt Universität Berlin, Berlin, Germany;
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and
¶ Institut National de la Santé et de la Recherche Médicale, Unité 580 and
|| Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France
Most peptide ligands presented by MHC class I molecules are the product of an intracellular pathway comprising protein breakdown in the cytosol, transport into the endoplasmic reticulum, and successive N-terminal trimming events. The efficiency of each of these processes depends on the amino acid sequence of the presented ligand and its precursors. Thus, relating the amino acid composition N-terminal of presented ligands to the sequence specificity of processes in the pathway gives insight into the usage of ligand precursors in vivo. Examining the amino acid composition upstream the true N terminus of MHC class I ligands, we demonstrate the existence of a distinct N-terminal processing motif comprising approximately seven residues and matching the known preferences of proteasome and TAP, two key players in ligand processing. Furthermore, we find that some residues, which are preferred by both TAP and the proteasome, are underrepresented at positions immediately preceding the N terminus of MHC class I ligands. Based on experimentally determined aminopeptidase activities, this pattern suggests trimming next to the final N terminus to take place predominantly in the endoplasmic reticulum.
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1 This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 490, E6, and Z3 to S.T. and H.S.), EU 6FP 503231 to H.S., Hochschulbauförderungsgesetz Programme HBFG-122-605 to H.S., and Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Grant U54 AI065359 to B.P.
2 M.M.S. and B.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Stefan Tenzer and Dr. Hansjörg Schild, Universitat Mainz, Hochhans au Argustoplatz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany. E-mail addresses: tenzer{at}uni-mainz.de and schild{at}uni-mainz.de
4 Abbreviations used in this paper: ER, endoplasmic reticulum; PA, protease assay; AMC, amino-4-methyl coumarin; RFU, real fluorescence units; F.A., formic acid.
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