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J. Biol. Chem., Vol. 276, Issue 32, 30050-30056, August 10, 2001
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From the Peptides presented to cytotoxic T lymphocytes by
the class I major histocompatability complex are 8-11 residues
long. Although proteasomal activity generates the precise C termini of
antigenic epitopes, the mechanism(s) involved in generation of the
precise N termini is largely unknown. To investigate the mechanism of N-terminal peptide processing, we used a cell-free system in which two
recombinant ornithine decarboxylase (ODC) constructs, one expressing
the native H2-Kb-restricted ovalbumin (ova)-derived
epitope SIINFEKL (ODC-ova) and the other expressing the extended
epitope LESIINFEKL (ODC-LEova), were targeted to degradation by 26 S
proteasomes followed by import into microsomes. We found that the
cleavage specificity of the 26 S proteasome was influenced by the
N-terminal flanking amino acids leading to significantly different
yields of the final epitope SIINFEKL. Following incubation in the
presence of purified 26 S proteasome, ODC-LEova generated largely
ESIINFEKL that was efficiently converted to the final epitope SIINFEKL
following translocation into microsomes. The conversion of ESIINFEKL to
SIINFEKL was strictly dependent on the presence of H2-Kb
and was completely inhibited by the metalloaminopeptidase inhibitor 1,10-phenanthroline. Importantly, the converting activity was resistant
to a stringent salt/EDTA wash of the microsomes and was only apparent
when transport of TAP, the transporter associated with antigen
processing, was facilitated. These results strongly suggest a crucial
role for a luminal endoplasmic reticulum-resident metalloaminopeptidase in the N-terminal trimming of major
histocompatability complex class I-associated peptides.
A Role for a Novel Luminal Endoplasmic Reticulum Aminopeptidase
in Final Trimming of 26 S Proteasome-generated Major Histocompatability
Complex Class I Antigenic Peptides*
,,, and
Department of Biochemistry, George S. Wise
Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel,
the § Division of Molecular Immunology, German Cancer
Research Center (DKFZ), 69120 Heidelberg, Germany, and the
¶ Department of Immunology, Institute for Cell Biology, University
of Tübingen, Auf der Morgenstelle 15, D-72076 Tübingen,
Germany
*
This research was supported by a grant from the
German-Israel Foundation (to Y. R. and F. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a Research Career Development Award from
the Israel Cancer Research Fund. To whom correspondence should be
addressed. Tel.: 972-3-640-7192; Fax: 972-3-640-6834; E-mail:
yuvalr@post.tau.ac.il.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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