Dynamical Characterization of Two Differentially Disease Associated MHC Class I Proteins in Complex with Viral and Self-Peptides

Narzi, Daniele; Becker, Caroline M.; Fiorillo, Maria Teresa; Uchańska-Ziegler, Barbara; Ziegler, Andreas; Böckmann, Rainer A.

doi:10.1016/j.jmb.2011.11.021

Cited by 70 publications

(82 citation statements)

References 73 publications

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“…Similar connections between electrostatic potential and the conformational flexibility of the binding groove have been proposed by others [31,43].…”

Section: Discussionsupporting

confidence: 81%

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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“…Similar connections between electrostatic potential and the conformational flexibility of the binding groove have been proposed by others [31,43].…”

Section: Discussionsupporting

confidence: 81%

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

et al. 2015

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“…10, 12, and 32). These variations are similar to those that have been observed in comparative molecular dynamics simulations of different peptides bound to the same class I MHC protein (6,7,10).…”

Section: Peptides Alter the Hydrogen/deuterium Exchange Behavior Of Tsupporting

confidence: 82%

“…At the nanosecond timescale, some insight can be gained from prior molecular dynamics simulations of the same class I MHC protein with different peptides bound, each of which showed peptide-dependent variations in the overall shape, positions, and stabilities of the ␣-helices of the peptide-binding groove (6,7,10). Although these studies did not address variation in the ␤-sheet floor of the binding groove, given the tight connectivity between peptides, the helices, and the ␤-sheet, a peptide dependence to motion within individual ␤-strands should not be surprising (indeed, the differences in peptide-HLA-A2 contacts in different complexes include multiple residues of the ␤-sheet (supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, with HLA-A2, the mobility of the region that undergoes a structural change upon binding of the A6 TCR was shown to vary with different peptides (10). This may not be a unique observation as similar effects are believed to contribute to differential T cell recognition of native and modified MART-1 peptides (6), and MHC flexibility can be altered by micropolymorphisms (7,14,15). As demonstrated by the A6 TCR, peptide-dependent MHC dynamics can impact TCR recognition by altering the barriers for conformational adjustments, influencing the entropic costs for receptor binding and shifting the populations of binding-competent states.…”

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confidence: 99%

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Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

Hawse¹,

Gloor²,

Ayres³

et al. 2013

Journal of Biological Chemistry

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Background: Peptide modulation of MHC flexibility can affect recognition by immune receptors. Results: Different peptides alter the flexibility of the MHC protein at sites around the peptide-binding groove. Conclusion: Peptide modulation of MHC flexibility is not limited to specific peptides or isolated regions. Significance: Peptide modulation of MHC flexibility indicates an extension of antigenicity from the peptide to the MHC.

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“…These data can also be interpreted on the basis of recent biophysical and computational analyses. Indeed, several studies have described an enhanced degree of flexibility and disorder of B*2705 and B*2704 peptide-binding cleft in comparison to that of B*2706 and B*2709 alleles [45][46][47]. This would influence the tapasin dependence, the folding dynamics and the stability of HLA-peptide complexes overall [46].…”

Section: Introductionmentioning

confidence: 99%

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryThe human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

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Dynamical Characterization of Two Differentially Disease Associated MHC Class I Proteins in Complex with Viral and Self-Peptides

Cited by 70 publications

References 73 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

Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

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