Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jan;96(1):110-8.
doi: 10.3324/haematol.2010.030924. Epub 2010 Oct 7.

The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family

Christina Bade-Döding  1 , Alex Theodossis, Stephanie Gras, Lars Kjer-Nielsen, Britta Eiz-Vesper, Axel Seltsam, Trevor Huyton, Jamie Rossjohn, James McCluskey, Rainer Blasczyk
Affiliations

The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family

Christina Bade-Döding et al. Haematologica. 2011 Jan.

Abstract

Background: Polymorphic differences between human leukocyte antigen (HLA) molecules affect the specificity and conformation of their bound peptides and lead to differential selection of the T-cell repertoire. Mismatching during allogeneic transplantation can, therefore, lead to immunological reactions.

Design and methods: We investigated the structure-function relationships of six members of the HLA-B*41 allelic group that differ by six polymorphic amino acids, including positions 80, 95, 97 and 114 within the antigen-binding cleft. Peptide-binding motifs for B*41:01, *41:02, *41:03, *41:04, *41:05 and *41:06 were determined by sequencing self-peptides from recombinant B*41 molecules by electrospray ionization tandem mass spectrometry. The crystal structures of HLA-B*41:03 bound to a natural 16-mer self-ligand (AEMYGSVTEHPSPSPL) and HLA-B*41:04 bound to a natural 11-mer self-ligand (HEEAVSVDRVL) were solved.

Results: Peptide analysis revealed that all B*41 alleles have an identical anchor motif at peptide position 2 (glutamic acid), but differ in their choice of C-terminal pΩ anchor (proline, valine, leucine). Additionally, B*41:04 displayed a greater preference for long peptides (>10 residues) when compared to the other B*41 allomorphs, while the longest peptide to be eluted from the allelic group (a 16mer) was obtained from B*41:03. The crystal structures of HLA-B*41:03 and HLA-B*41:04 revealed that both alleles interact in a highly conserved manner with the terminal regions of their respective ligands, while micropolymorphism-induced changes in the steric and electrostatic properties of the antigen-binding cleft account for differences in peptide repertoire and auxiliary anchoring.

Conclusions: Differences in peptide repertoire, and peptide length specificity reflect the significant functional evolution of these closely related allotypes and signal their importance in allogeneic transplantation, especially B*41:03 and B*41:04, which accommodate longer peptides, creating structurally distinct peptide-HLA complexes.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The crystal structures of B*41:03/AEMYGSVTEHPSPSPL and B*41:04/HEEAVSVDRVL. View of the antigen-binding cleft in (A) the B*41:03/16mer and (B) the B*41:04/11mer complexes, as well as a superposition of the B*41:03/16mer and B*41:04/11mer structures using the Cα atoms of heavy chain residues 2-181 (C). The α-1/α-2 domains of the two alleles superimpose very well with an rms deviation of 0.33 Å. Therefore, only that of B*41:04 is presented in 1C. In each case the MHC is presented in cartoon format (B*41:03, green; B*41:04, blue) and the α-2 helix of the heavy chain has been removed for clarity. The peptide residues are drawn as sticks (16mer, light red; 11mer dark red), as are selected side chains of the MHC. Peptide residues are labeled in italics. The polymorphic residues distinguishing the two alleles are also shown, highlighting the size/charge differences associated with the R97S/N114D substitutions. In the case of the B*41:03/16mer complex (A, C), the central disordered region of the peptide was modeled and is presented here in ribbon format. The superposition (C) demonstrates that the N- and C-terminal regions of the two peptides adopt equivalent conformations, while the central region of the 16mer is expected to diverge significantly in conformation with respect to the 11mer. Moreover, the superposition also helps to highlight the significant difference in surface area that each peptide might present to T-cell receptor. Based on the modeled central region, the 16mer peptide is expected to have an exposed surface that is 650 Å2 greater than that of the 11mer when bound to one of the B*41 alleles (determined using the CCP4i implementation of AREAIMOL.,
Figure 2.
Figure 2.
Peptides bound to B*41:03 and B*41:04. Peptides bound to B*41:03 and B*41:04 display similarities at positions p1, p3 and pΩ-1 by occupying equivalent positions and interacting in a similar manner with the heavy chain. Views of the individual antigen-binding cleft pockets in the B*41:03/16mer and B*41:04/11mer structures. In all figures the MHC are presented in ribbon format, with key residue side chains shown as sticks. The peptides are presented in a combination of ribbon and stick format. B*41:03 is illustrated in green and B*41:04 in blue, while the 16mer and 11mer peptides are colored light and dark red, respectively. Hydrogen bond and salt bridge interactions are shown as blue dashes, while selected VDW contacts are shown as orange dashes. Peptide residues are labeled in italics. (A, B) Pocket A composition of B*41 variants. p1 interactions in the B*41:03/16-mer (A) and B*41:04/11-mer structures (B). In both B*41 molecules, the residues contacting p1 of the peptide are conserved at positions 7, 63, 159, 167 and 171 (pocket A). (C, D) Pocket B composition of B*41 variants. p2 interactions in the B*41:03/16-mer (C) and B*41:04/11-mer structures (D). Positions 7, 9, 24, 45, 63, 66, 67, 99 and 159 are in contact with p2 of the peptide. p2 of B*41:03 is also anchored by residue 62. Arg62 is not part of pocket B in B*41:04 (D) and it is guanidinium group appears disordered, highlighted in (D) using a partially transparent stick representation. (E, F) p3 of the peptides is in contact with R97 of B*41:03 but not with S97of B*41:04. p3 interactions in the B*41:03/16-mer (E) and B*41:04/11-mer structures (F). Positions 66, 99, 155, 156 and 159 are in contact with p3 of the peptide. The polymorphic residue 97 distinguishing B*41:03 and B*41:04 does not anchor p3 of the peptide bound to B*41:04 (F), but is part of pocket D for B*41:03 (E). The side chain of p3 is observed in two distinct conformations in the B*41:03/11mer structure (E), each of which was refined at 50% occupancy. The two conformers interact alternately with either position 97 or 156 of th MHC, and are distinguished in (E) using a partially transparent stick representation for one, but not the other. (G, H): Contacts between the heavy chain and position pΩ-1 of the bound peptides. pΩ-1 interactions in the B*41:03/16-mer (G) and B*41:04/11-mer structures (H). p15 of the ligand bound to B*41:03 and p10 of the ligand bound to B*41:04 are in contact with conserved HLA heavy chain residues 73, 76, 77 and 147, which anchor peptide positions pΩ-1 in both subtypes. (I, J) Position 97 and 114 are not part of pocket F in B41 variants. pΩ interactions in the B*41:03/16-mer (I) and B*41:04/11-mer structures (J). This figure shows the composition of residues contacting the C-terminal position of the peptide, namely L16 for B*41:03 and L11 for B*41:04. Positions 77, 80, 84, 95, 116, 123 143, 146 and 147 are in contact with the pΩ position of the peptide. B*41:03 and B*41:04 share the same F pocket composition. Residues 97 and 114 are not part of the F pocket of B*41 subtypes. For this reason, mismatches at these positions will not alter the C-terminal binding motif in B*41 subtypes.
Figure 3.
Figure 3.
A conserved network of interactions in the B*41:03/16mer and B*41:04/11mer complexes. Detail of the antigen-binding cleft in (A) the B*41:03/16mer and (B) the B*41:04/11mer structures, showing a conserved network of interactions involving position p3, and the heavy chain positions 114 and 156. In each case the MHC and peptide are shown in ribbon format, with key residue side chains drawn as sticks. Key interactions are represented by dashes. Hydrogen bonds are shown in blue, VDW contacts in orange, and potential salt bridge interactions in ‘wheat’. The network is maintained in both alleles, despite the unfavorable Asn114Asp in B*41:04. Ordered water molecules within interacting distance of the charged groups are shown as semi-transparent spheres.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chelvanayagam G. A roadmap for HLA-A, HLA-B, and HLA-C peptide binding specificities. Immunogenetics. 1996;45(1):15–26. - PubMed
    1. Vyas JM, Van der Veen AG, Ploegh HL. The known unknowns of antigen processing and presentation. Nat Rev Immunol. 2008;8 (8):607–18. - PMC - PubMed
    1. Kim Y, Sidney J, Pinilla C, Sette A, Peters B. Derivation of an amino acid similarity matrix for peptide: MHC binding and its application as a Bayesian prior. BMC Bioinformatics. 2009;10:394. - PMC - PubMed
    1. Zhao Y, Gran B, Pinilla C, Markovic-Plese S, Hemmer B, Tzou A, et al. Combinatorial peptide libraries and biometric score matrices permit the quantitative analysis of specific and degenerate interactions between clonotypic TCR and MHC peptide ligands. J Immunol. 2001;167(4):2130–41. - PubMed
    1. Zhang C, Bickis MG, Wu FX, Kusalik AJ. Optimally-connected hidden Markov models for predicting MHC-binding peptides. J Bioinform Comput Biol. 2006;4(5):959–80. - PubMed

Publication types

MeSH terms