Position 156 influences the peptide repertoire and tapasin dependency of human leukocyte antigen B*44 allotypes

Badrinath, S; Saunders, Philippa M.; Huyton, Trevor; Aufderbeck, Susanne; Hiller, Oliver; Blasczyk, Rainer; Bade‐Doeding, Christina

doi:10.3324/haematol.2011.046037

Cited by 31 publications

(45 citation statements)

References 27 publications

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“…Additionally, the stronger tapasin dependence of HLA-B*4402 compared to HLA-B*4405 and HLA-B*2705 is consistent with previous findings (25, 27). The strong tapasin dependence of HLA-B*0801, HLA-B*4402, HLA-B*4403, HLA-B*5101 and HLA-B*5701, and the strong tapasin-independence of HLA-B*3501 is also consistent with previous findings (32, 40, 41). HLA-B molecules are grouped into one of two serotypes, HLA-Bw4 and HLA-Bw6, which differ at residues 77–83 of the heavy chain α1 domain (42).…”

Section: Resultssupporting

confidence: 92%

Distinct Assembly Profiles of HLA-B Molecules

Rizvi¹,

Salamati²,

Geng³

et al. 2014

The Journal of Immunology

139

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Major histocompatibility complex (MHC) class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers and inflammatory diseases. Human MHC class I heavy chains are encoded by the HLA-A, HLA-B and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to distinct set of peptide antigens, which are presented to CD8+ T cells. HLA-disease associations have been shown in some cases to link to the peptide binding characteristics of individual HLA class I molecules. Here we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin-independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules, and indicate influences of HLA-B folding patterns upon infectious disease outcomes.

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Section: Resultssupporting

confidence: 92%

Distinct Assembly Profiles of HLA-B Molecules

Rizvi¹,

Salamati²,

Geng³

et al. 2014

The Journal of Immunology

139

View full text Add to dashboard Cite

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“…Among the two allotypes that were entirely US3-resistant, HLA-A*0301 adheres to the rule (R114), whereas HLA-C*0702 violates it (D114). However, substitutions of amino acids in positions 116 or 156 can likewise have a decisive influence on tapasin dependence or independence on the background of certain allotypes (52,53). Thus, our data do not argue against a connection between tapasin dependence and US3 sensitivity of HLA allotypes, but the relationship between amino acid sequence and US3 sensitivity seems to be too complex to be guided by a single amino acid position.…”

Section: Discussionmentioning

confidence: 56%

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

Ameres

Besold

Plachter

et al. 2014

The Journal of Immunology

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Immunoevasive proteins (“evasins”) of human CMV (HCMV) modulate stability and localization of MHC class I (MHC I) molecules, and their supply of antigenic peptides. However, it is largely unknown to what extent these evasins interfere with recognition by virus-specific CD8 T cells. We analyzed the recognition of HCMV-infected cells by a panel of CD8 T cells restricted through one of nine different MHC I allotypes. We employed a set of HCMV mutants deleted for three or all four of the MHC I modulatory genes US2, US3, US6, and US11. We found that different HCMV evasins exhibited different allotype-specific patterns of interference with CD8 T cell recognition of infected cells. In contrast, recognition of different epitopes presented by the same given MHC I allotype was uniformly reduced. For some allotypes, single evasins largely abolished T cell recognition; for others, a concerted action of evasins was required to abrogate recognition. In infected cells whose Ag presentation efficiency had been enhanced by IFN-γ pretreatment, HCMV evasins cooperatively impared T cell recognition for several different MHC I allotypes. T cell recognition and MHC I surface expression under influence of evasins were only partially congruent, underscoring the necessity to probe HCMV immunomodulation using specific T cells. We conclude that the CD8 T cell evasins of HCMV display MHC I allotype specificity, complementarity, and cooperativity.

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“…Since B*27:05 and B*27:09 differ by only one amino acid and yet are differentially associated with ankylosing spondylitis, the molecular and cellular differences between the two subtypes have been intensely investigated [31,36,[39][40][41][42]. We have focused here on comparing their conformational stabilities through a combined theoretical and experimental investigation.…”

Section: Discussionmentioning

confidence: 99%

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...

show abstract

Position 156 influences the peptide repertoire and tapasin dependency of human leukocyte antigen B*44 allotypes

Cited by 31 publications

References 27 publications

Distinct Assembly Profiles of HLA-B Molecules

Distinct Assembly Profiles of HLA-B Molecules

CD8 T Cell–Evasive Functions of Human Cytomegalovirus Display Pervasive MHC Allele Specificity, Complementarity, and Cooperativity

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

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