Structural and functional mosaic nature of MHC class I molecules in their peptide-free form

Kurimoto, Eiji; Kuroki, Kazuhiko; Yamaguchi, Yoshiki; Yagi-Utsumi, Maho; Igaki, T.; Iguchi, Takeshi; Maenaka, Katsumi; Kato, Koichi

doi:10.1016/j.molimm.2013.03.014

Cited by 34 publications

(32 citation statements)

References 37 publications

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“…1 show that suboptimally loaded B*27:05 has difficulties to tightly bind β 2 m and pass the cellular conformational quality control. We recently have shown that the conformational restriction of the F pocket region by a disulfide bond (C84-C139) helps the binding of β 2 m to the heavy chain through conformational and dynamic effects that stabilize the folded conformation of class I and help it pass ER quality control [44].In agreement with our findings, the recent nuclear magnetic resonance spectroscopy work of Kurimoto et al suggests that in the absence of peptide, on a long timescale, the α 1 and α 2 domains of HLA-C may become entirely unfolded, with only the α 3 domain remaining structured [45]. The propensity of newly synthesized B*27:05 to misfold and aggregate has long been suggested to correlate with AS etiology [46][47][48][49].…”

supporting

confidence: 91%

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

et al. 2015

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The human MHC class I protein HLA-B*27:05 is statistically associated with ankylosing spondylitis, unlike HLA-B*27:09, which differs in a single amino acid in the F pocket of the peptide-binding groove. To understand how this unique amino acid difference leads to a different behavior of the proteins in the cell, we have investigated the conformational stability of both proteins using a combination of in silico and experimental approaches. Here, we show that the binding site of B*27:05 is conformationally disordered in the absence of peptide due to a charge repulsion at the bottom of the F pocket. In agreement with this, B*27:05 requires the chaperone protein tapasin to a greater extent than the conformationally stable B*27:09 in order to remain structured and to bind peptide. Taken together, our data demonstrate a method to predict tapasin dependence and physiological behavior from the sequence and crystal structure of a particular class I allotype.Keywords: Ankylosing spondylitis r HLA-B27 r Major histocompatibility complex r Molecular dynamics r Natively unstructured proteins r Protein folding r Simulations Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction MHC class I molecules are heterotrimeric proteins that transport antigenic peptides to the cell surface and present them to cytotoxic T cells. They consist of the transmembrane heavy chain (HC), the noncovalently associated light chain beta-2 microglobulin (β 2 m), and an antigenic peptide of eight to ten amino acids. The Correspondence: Prof. Sebastian Springer e-mail: s.springer@jacobs-university.de extracellular part of the heavy chain comprises the α 1 , α 2 , and α 3 domains. The α 1 and α 2 domains form the peptide-binding groove, a superdomain that consists of an antiparallel beta sheet surmounted by two alpha helices, between which the peptide binds [1,2].In the cell, peptide binding to class I is a multistep process within the ER. It involves the peptide-loading complex, which consists of the peptide transporter associated with antigen processing (TAP) that transports peptides from the cytosol into the ER lumen [3] and several chaperone proteins such as tapasin, which binds both to the class I molecule and TAP [4,5].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1248-1257 Molecular immunology 1249The sequence of peptides that can bind to class I is determined by interactions with the amino acid side chains of the peptide-binding groove. The high sequence polymorphism of the peptide-binding groove in human class I molecules (human leukocyte antigens, HLA-A, -B, and -C) means that different allotypes bind different peptides; thus, individual HLA allotypes-such as HLA-B27-support-specific immune responses and are statistically associated with disease [6,7]. Among the subtypes of HLA-B27 [8,9], HLA-B*27:05 (B*27:05) shows a very strong statistical association with spondyloarthropathies such as ankylosing spondylitis (AS), in contr...

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confidence: 91%

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

et al. 2015

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“…The simplest explanation for this effect is that, in the presence of the dipeptides, the structure of class I is more conducive to the binding of full-length peptide. Recently, the α 1 /α 2 domain of class I molecules that lack high-affinity peptide was shown to be significantly structurally disordered (24)(25)(26), and we propose that the dipeptides bind into the F pocket region to alleviate this molecular disorder. Because of their low affinity to class I (in the lower millimolar range; Fig.…”

Section: Discussionmentioning

confidence: 90%

Dipeptides promote folding and peptide binding of MHC class I molecules

Saini

Ostermeir

Ramnarayan

et al. 2013

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

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MHC class I molecules bind only those peptides with high affinity that conform to stringent length and sequence requirements. We have now investigated which peptides can aid the in vitro folding of class I molecules, and we find that the dipeptide glycyl-leucine efficiently supports the folding of HLA-A*02:01 and H-2K b into a peptide-receptive conformation that rapidly binds high-affinity peptides. Treatment of cells with glycyl-leucine induces accumulation of peptide-receptive H-2K b and HLA-A*02:01 at the surface of cells. Other dipeptides with a hydrophobic second amino acid show similar enhancement effects. Our data suggest that the dipeptides bind into the F pocket like the C-terminal amino acids of a highaffinity peptide.antigen presentation | ligand exchange | chemical chaperones | endoplasmic reticulum | quality control M HC class I molecules are transmembrane proteins that are vital to the mammalian antiviral and antitumor immune response. They bind intracellular peptides in the lumen of the endoplasmic reticulum (ER) to transport them to the cell surface for inspection by cytotoxic T lymphocytes. To elicit a sustained immune response, peptides need to form stable complexes with class I molecules (1, 2), which means that they must conform to specific length and sequence requirements that were first identified by elution and sequencing, and then structurally understood by X-ray crystallography. Depending on the class I allotype, high-affinity peptides must be 8 to 10 aa long (such that the termini can form hydrogen bonding networks) and have defined side chains at particular positions that bind into specificity pockets at the bottom of the binding groove (3-5). This knowledge has been used to predict the binding affinity of any peptide sequence to a given class I allotype (6), and, together with theoretical simulations of the conformational movements of class I-peptide complexes, it has allowed the design of altered peptide ligands with higher binding affinities (7). The high-affinity peptides thus identified can be used to fold many bacterially expressed denatured class I molecules into their native state (8). Consequently, high-affinity peptides have been called the "essential third subunit of MHC class I" (9).In living cells, class I molecules bind high-affinity peptides with the help of several chaperone proteins, collectively called the peptide loading complex (PLC). Importantly, experiments in vivo and in vitro have shown that, in the presence of the PLC, peptide loading is iterative, i.e., class I molecules first bind suboptimal peptides (peptides that are too long, too short, or do not have the requisite anchor residues) and gradually exchange them for higher-affinity ones (10, 11). The idea that class I molecules can initially fold with such suboptimal peptides is indeed supported by the crystal structures of several class I molecules with octamer or pentamer peptides (12, 13).In our effort to determine the minimum peptide requirements for the folding of class I, we have analyzed even smaller p...

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“…Further investigation of K b -Y84C might elucidate this coupling, which is central to MHC-I stability and to the molecular understanding of cellular peptide selection. To analyze conformational dynamics, novel tools are required; as the investigation of heavy-chain-b 2 m interactions by nuclear magnetic resonance spectroscopy is only just emerging Kurimoto et al, 2013), we think that molecular dynamics analyses with extended simulation times and more refined analytical methods will remain an important tool.…”

Section: Discussionmentioning

confidence: 99%

“…by UGT1). Second, tapasin -in addition to its effect on peptide exchange and optimization (Williams et al, 2002;Chen and Bouvier, 2007;Wearsch and Cresswell, 2007) -helps to structure the peptidebinding site of suboptimally loaded (and thus conformationally disordered) MHC-I molecules, such that they can bind peptide (Kienast et al, 2007;Garstka et al, 2011;Kurimoto et al, 2013). The efficient surface transport of K b -Y84C in tapasin-deficient cells (Figs 4, 6) might be at least partially caused by the ordering of the F-pocket region by the C84-C139 disulfide bond, which thus substitutes for tapasin.…”

Section: Discussionmentioning

confidence: 99%

“…Suboptimally loaded MHC-I have a decreased affinity to b 2 m, lower thermal stability, a larger hydrodynamic radius and greater conformational mobility of individual residues compared to highaffinity peptide-bound MHC-I (Elliott et al, 1991;Fahnestock et al, 1992;Springer et al, 1998;Mage et al, 2012;Kurimoto et al, 2013); thus, suboptimally loaded MHC-I molecules have been compared to molten globules (Bouvier and Wiley, 1998;Saini et al, 2013). In support of this view, comparative molecular dynamics simulations on empty and peptide-bound murine and human MHC-I have indicated a substantially increased mobility of peptide-empty MHC-I, especially in those parts of the a 1 and a 2 helices that delineate the F-pocket (Sieker et al, 2007;Sieker et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Hein

Uchtenhagen

Abualrous

et al. 2014

Journal of Cell Science

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The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, K b -Y84C, in which two a-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound highaffinity peptide. K b -Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (b 2 m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and b 2 m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by b 2 m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that b 2 m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.

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Structural and functional mosaic nature of MHC class I molecules in their peptide-free form

Cited by 34 publications

References 37 publications

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

F pocket flexibility influences the tapasin dependence of two differentially disease‐associated MHC Class I proteins

Dipeptides promote folding and peptide binding of MHC class I molecules

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

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