Structure of the human class I histocompatibility antigen, HLA-A2

Björkman, Pamela J.; Saper, Mark A.; Samraoui, B.; Bennett, William S.; Strominger, Jack L.; Wiley, Don C.

doi:10.1038/329506a0

Cited by 3,311 publications

(1,592 citation statements)

References 49 publications

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“…NO1-CO-56000. critical for peptide binding and are therefore thought to be critical for T cell recognition 9 and represent the functional part of the molecule. Further, patterns of mutational substitutions within the PBR have affirmed the strong role of historic selection pressures in preserving functional variation, likely with peptide binding consequences, for this region.…”

Section: Correspondence: Stephen J O'brien Phd Laboratory Of Genomimentioning

confidence: 99%

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Taxonomic hierarchy of HLA class I allele sequences

et al. 1999

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The markedly high levels of polymorphism present in classical class I loci of the human major histocompatibility complex have been implicated in infectious and immune disease recognition. The large numbers of alleles present at these loci have, however, limited efforts to verify associations between individual alleles and specific diseases. As an approach to reduce allele diversity to hierarchical evolutionarily related groups, we performed phylogenetic analyses of available HLA-A, B and C allele complete sequences (n = 216 alleles) using different approaches (maximum parsimony, distance-based minimum evolution and maximum likelihood). Full nucleotide and amino acid sequences were considered as well as abridged sequences from the hypervariable peptide binding region, known to interact in vivo, with HLA presented foreign peptide. The consensus analyses revealed robust clusters of 36 HLA-C alleles concordant for full and PBR sequence analyses. HLA-A alleles (n = 60) assorted into 12 groups based on full nucleotide and amino acid sequence which with few exceptions recapitulated serological groupings, however the patterns were largely discordant with clusters prescribed by PBR sequences. HLA-B which has the most alleles (n = 120) and which unlike HLA-A and -C is thought to be subject to frequent recombinational exchange, showed limited phylogenetic structure consistent with recent selection driven retention of maximum heterozygosity and population diversity. Those allele categories recognized offer an explicit phylogenetic criterion for grouping alleles potentially relevant for epidemiologic associations, for inferring the origin of MHC genome organization, and for comparing functional constraints in peptide presentation of HLA alleles.

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Section: Correspondence: Stephen J O'brien Phd Laboratory Of Genomimentioning

confidence: 99%

“…These domains form the peptide binding region (PBR). 9,10 Fifty-seven residues within the PBR have been identified as being…”

Section: Introductionmentioning

confidence: 99%

Taxonomic hierarchy of HLA class I allele sequences

et al. 1999

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“…Furthermore, binding and mutational analyses of naturally processed peptides have identified critical anchor residues that interact with the binding pockets of the MHC molecules and, thus, help establish the preferred binding motif. In addition, the protein crystal structures of both class I and class II MHC molecules have been invaluable in delineating the biophysical nature of peptide-MHC interactions as well as the TCR-mediated recognition of peptide-MHC complexes (examples in [15][16][17][18]). …”

Section: Introductionmentioning

confidence: 99%

Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells

et al. 2006

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This report details the biochemical features of natural peptides selected by the H-2K d class I MHC molecule. In normal cell lines, the length of the naturally processed peptides ranged from 8 to 18 amino acids, although the majority were 9-mers (16% were longer than nine residues). The binding motif for the 9-mer peptides was dominated by the presence of a tyrosine at P2 and an isoleucine/leucine at the P9 position. The P2 residue contributed most towards binding; and the short peptides bound better and formed longer-lived cell surface complexes than the long peptides, which bound poorly and dissociated rapidly. The longer peptides did not exhibit this strictly defined motif. Trimming the long peptides to their shorter forms did not enhance binding and conversely, extending the 9-mer peptides did not decrease binding. The long peptides were present on the cell-surface bound to H-2K d (Kd) and were not intermediate products of the class I MHC processing pathway. Finally, in two different TAP-deficient cells the long peptides were the dominant species, which suggested that TAPindependent pathways selected for long peptides by class I MHC molecules.

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“…β2m has the typical immunoglobin β-sandwich fold, consisting of seven β-strands organized in two β-sheets of antiparallel β-strands. 9 The first sheet comprises four strands (ABED) and the second sheet consist of three strands (CFG). The native structure is stabilized by a disulphide bond between Cys25 (strand B) and Cys80 (strand F).…”

Section: Introductionmentioning

confidence: 99%

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2‐microglobulin: A molecular dynamics simulation study

Narang

Shuaib

Goyal

2017

J of Cellular Biochemistry

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Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic β2-microglobulin (β2m) protein around skeletal joints and bones. The recent studies highlighted a critical role of the DE loop region for β2m stability and amyloid aggregation propensity. Despite significant efforts, the molecular mechanism of enhanced aggregation due to D59P mutation in the DE loop region remain elusive. In the present study, explicit-solvent molecular dynamics (MD) simulations were performed to examine the key changes in the structural and dynamic properties of wild type (wt) β2m upon D59P mutation. MD simulations reveal a decrease in the average number of hydrogen bonds in the loop regions on D59P mutation that enhances conformational flexibility, which lead to higher aggregation propensity of D59P as compare to wt β2m. The principal component analysis (PCA) highlight that D59P covers a larger region of phase space and display a higher trace value than wt β2m, which suggest an overall enhancement in the conformational flexibility. D59P display two minimum energy basins in the free energy landscape (FEL) that are associated with thermodynamically less stable conformational states as compare to single minimum energy basin in wt β2m. The present study provides theoretical insights into the molecular mechanism behind the higher aggregation propensity of D59P as compare to wt β2m. K E Y W O R D Samyloid aggregation, β2-microglobulin, D59P mutation, DE loop, molecular dynamics

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Structure of the human class I histocompatibility antigen, HLA-A2

Cited by 3,311 publications

References 49 publications

Taxonomic hierarchy of HLA class I allele sequences

Taxonomic hierarchy of HLA class I allele sequences

Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2‐microglobulin: A molecular dynamics simulation study

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Structure of the human class I histocompatibility antigen, HLA-A2

Cited by 3,311 publications

References 49 publications

Taxonomic hierarchy of HLA class I allele sequences

Taxonomic hierarchy of HLA class I allele sequences

Identification of naturally processed peptides bound to the class I MHC molecule H‐2Kd of normal and TAP‐deficient cells

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2‐microglobulin: A molecular dynamics simulation study

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Identification of naturally processed peptides bound to the class I MHC molecule H‐2K^d of normal and TAP‐deficient cells