Peptide-independent stabilization of MHC class I molecules breaches cellular quality control*

Hein, Zeynep; Uchtenhagen, Hannes; Abualrous, Esam T.; Saini, Sunil Kumar; Janssen, L. W.; Hateren, Andy van; Wiek, Constanze; Hanenberg, Helmut; Momburg, Frank; Achour, Adnane; Elliott, Tim; Springer, Sebastian; Boulanger, D.

doi:10.1242/jcs.145334

Cited by 64 publications

(102 citation statements)

References 95 publications

(83 reference statements)

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“…Evaluation of association and dissociation parameters of a battery of peptides, containing targeted departures from the model, revealed that peptide acquisition by H-2K b takes place in two distinct phases. During the first phase, the peptide-binding groove of H-2K b accepts a wide range of candidates, including even amino acid side chains much larger than their optimal size, which implies significant flexibility in the anchor residue-accepting pockets (17,(19)(20)(21)(22). Following the initial association event, ill-suited peptides exhibit greater propensity for dissociation and are thus selected against.…”

Section: Discussionmentioning

confidence: 99%

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The first step of peptide selection in antigen presentation by MHC class I molecules

Garstka¹,

Fish

Celie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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MHC class I molecules present a variable but limited repertoire of antigenic peptides for T-cell recognition. Understanding how peptide selection is achieved requires mechanistic insights into the interactions between the MHC I and candidate peptides. We find that, at first encounter, MHC I H-2K b considers a wide range of peptides, including those with expanded N termini and unfitting anchor residues. Discrimination occurs in the second step, when noncanonical peptides dissociate with faster exchange rates. This second step exhibits remarkable temperature sensitivity, as illustrated by numerous noncanonical peptides presented by H-2K b in cells cultured at 26°C relative to 37°C. Crystallographic analyses of H-2K b -peptide complexes suggest that a conformational adaptation of H-2K b drives the decisive step in peptide selection. We propose that MHC class I molecules consider initially a large peptide pool, subsequently refined by a temperature-sensitive induced-fit mechanism to retain the canonical peptide repertoire.antigen presentation | peptide binding | anchor residues | dynamics | entropy M HC class I molecules present a wide array of peptides to cytotoxic T lymphocytes, allowing the immune system to scan for intracellular pathogens and mutated proteins. These peptides are not chosen at random, but rather are selected for their ability to bind to the polymorphic MHC class I peptidebinding groove. Antigenic peptide precursors are produced by the proteasome and further trimmed by cytosolic aminopeptidases. They are translocated into the endoplasmic reticulum (ER) lumen by the peptide transporter TAP that has broad peptide specificity. Peptides can be further trimmed in the ER lumen by ER aminopeptidases before selection by a defined MHC class I allele (reviewed in ref. 1). Only few peptides from a broad peptidome are presented by a given MHC class I allele. How a defined MHC I allele selects the correct peptides for presentation out of a large and diverse peptide pool is unclear.In principle, MHC class I molecules could consider only "optimal" peptides and ignore the remainder of the TAPtranslocated peptidome. Alternatively, MHC class I could bind all available peptides followed by a selection step for the optimal candidates for presentation. To discriminate between these scenarios, we studied peptide association (on-rates) and dissociation (off-rates) from the mouse MHC class I molecule H-2K b . To characterize the biophysical basis of discrimination between candidate peptides we complemented the kinetic data with five crystal structures of H-2K b with peptide variants. A comprehensive analysis of our in vitro data indicated that discrimination against suboptimal peptides by MHC class I may exhibit a strong temperature dependency, as illustrated by the H-2K b peptidome from cells cultured at 26°C versus 37°C. We thus arrive at a two-step model for peptide selection by MHC class I molecules, which explains how not so "empty MHC class I molecules come out in the cold" (2).

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Section: Discussionmentioning

confidence: 99%

“…Structural Flexibility in the Peptide-Binding Groove of H-2K b . The peptide-binding groove should be flexible to accommodate expanded anchors (17)(18)(19)(20)(21)(22) (Table S4). In all structures the peptides could be resolved and fit into the electron density (Fig.…”

Section: Association and Disassociation Kinetics Of 9-mer Peptide Varmentioning

confidence: 99%

The first step of peptide selection in antigen presentation by MHC class I molecules

Garstka¹,

Fish

Celie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The unfolded protein fraction was calculated from the mean residue ellipticity (u) according to the following standard method: fraction unfolded (%) = (u 2 uN)/(uU 2 uN), where uN and uU are the mean residue ellipticity values in the fully folded and fully unfolded states, respectively. The melting temperature (Tm) was determined by fitting the data to the denaturation curves with the Origin 8.0 program (Origin Lab) as previously described (28)(29)(30).…”

Section: Thermostability Of P/uaa-b2mmentioning

confidence: 99%

The Structure of the MHC Class I Molecule of Bony Fishes Provides Insights into the Conserved Nature of the Antigen-Presenting System

Chen

Zhang

et al. 2017

The Journal of Immunology

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MHC molecules evolved with the descent of jawed fishes some 350–400 million years ago. However, very little is known about the structural features of primitive MHC molecules. To gain insight into these features, we focused on the MHC class I Ctid-UAA of the evolutionarily distant grass carp (Ctenopharyngodon idella). The Ctid-UAA H chain and β2-microglobulin (Ctid-β2m) were refolded in vitro in the presence of peptides from viruses that infect carp. The resulting peptide-Ctid-UAA (p/Ctid-UAA) structures revealed the classical MHC class I topology with structural variations. In comparison with known mammalian and chicken peptide-MHC class I (p/MHC I) complexes, p/Ctid-UAA structure revealed several distinct features. Notably, 1) although the peptide ligand conventionally occupied all six pockets (A–F) of the Ag-binding site, the binding mode of the P3 side chain to pocket D was not observed in other p/MHC I structures; 2) the AB loop between β strands of the α1 domain of p/Ctid-UAA complex comes into contact with Ctid-β2m, an interaction observed only in chicken p/BF2*2101-β2m complex; and 3) the CD loop of the α3 domain, which in mammals forms a contact with CD8, has a unique position in p/Ctid-UAA that does not superimpose with the structures of any known p/MHC I complexes, suggesting that the p/Ctid-UAA to Ctid-CD8 binding mode may be distinct. This demonstration of the structure of a bony fish MHC class I molecule provides a foundation for understanding the evolution of primitive class I molecules, how they present peptide Ags, and how they might control T cell responses.

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“…Retroviral expression, microscopy and flow cytometry Retroviral expression, microscopy and flow cytometry were performed as in Hein et al, 2014.…”

Section: Cellsmentioning

confidence: 99%

The murine cytomegalovirus immunoevasin gp40 binds MHC class I molecules to retain them in the early secretory pathway

Janssen

Ramnarayan

Abo-Elmagd

et al. 2016

Journal of Cell Science

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In the presence of the murine cytomegalovirus (mCMV) gp40 (m152) protein, murine major histocompatibility complex (MHC) class I molecules do not reach the cell surface but are retained in an early compartment of the secretory pathway. We find that gp40 does not impair the folding or high-affinity peptide binding of the class I molecules but binds to them, leading to their retention in the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment (ERGIC) and the cis-Golgi, most likely by retrieval from the cis-Golgi to the ER. We identify a sequence in gp40 that is required for both its own retention in the early secretory pathway and for that of class I molecules.

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Peptide-independent stabilization of MHC class I molecules breaches cellular quality control*

Cited by 64 publications

References 95 publications

The first step of peptide selection in antigen presentation by MHC class I molecules

The first step of peptide selection in antigen presentation by MHC class I molecules

The Structure of the MHC Class I Molecule of Bony Fishes Provides Insights into the Conserved Nature of the Antigen-Presenting System

The murine cytomegalovirus immunoevasin gp40 binds MHC class I molecules to retain them in the early secretory pathway

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