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J Immunol. 2015 Nov 1;195(9):4503-13. doi: 10.4049/jimmunol.1501515. Epub 2015 Sep 28.

Mechanistic Basis for Epitope Proofreading in the Peptide-Loading Complex.

Author information

1
Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany;
2
Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780 Bochum, Germany; and.
3
Molecular Life Science, Jacobs University Bremen, 28759 Bremen, Germany.
4
Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany; tampe@em.uni-frankfurt.de.

Abstract

The peptide-loading complex plays a pivotal role in Ag processing and is thus central to the efficient immune recognition of virally and malignantly transformed cells. The underlying mechanism by which MHC class I (MHC I) molecules sample immunodominant peptide epitopes, however, remains poorly understood. In this article, we delineate the interaction between tapasin (Tsn) and MHC I molecules. We followed the process of peptide editing in real time after ultra-fast photoconversion to pseudoempty MHC I molecules. Tsn discriminates between MHC I loaded with optimal and MHC I bound to suboptimal cargo. This differential interaction is key to understanding the kinetics of epitope proofreading. To elucidate the underlying mechanism at the atomic level, we modeled the Tsn/MHC I complex using all-atom molecular dynamics simulations. We present a catalytic working cycle, in which Tsn binds to MHC I with suboptimal cargo and thereby adjusts the energy landscape in favor of MHC I complexes with immunodominant epitopes.

PMID:
26416272
DOI:
10.4049/jimmunol.1501515
[Indexed for MEDLINE]
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