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.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Epitopes / chemistry
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Epitopes / genetics
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Epitopes / metabolism*
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Fluorescence Polarization
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HLA-B44 Antigen / chemistry
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HLA-B44 Antigen / genetics
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HLA-B44 Antigen / metabolism
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Histocompatibility Antigens Class I / chemistry
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / metabolism*
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Humans
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Immunodominant Epitopes / chemistry
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Immunodominant Epitopes / genetics
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Immunodominant Epitopes / metabolism
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Kinetics
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Membrane Transport Proteins / chemistry
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism*
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Molecular Dynamics Simulation
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Mutation
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Peptides / chemistry
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Peptides / genetics
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Peptides / metabolism*
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Protein Binding
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Protein Disulfide-Isomerases / chemistry
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Protein Disulfide-Isomerases / genetics
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Protein Disulfide-Isomerases / metabolism
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Protein Structure, Tertiary
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Thermodynamics
Substances
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Epitopes
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HLA-B44 Antigen
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Histocompatibility Antigens Class I
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Immunodominant Epitopes
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Membrane Transport Proteins
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Peptides
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tapasin
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Protein Disulfide-Isomerases
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PDIA3 protein, human