Elsevier

Human Immunology

Volume 64, Issue 7, July 2003, Pages 718-728
Human Immunology

Original contribution
Compression of functional space in HLA-A sequence diversity

https://doi.org/10.1016/S0198-8859(03)00078-8Get rights and content

Abstract

The major histocompatibility complex (MHC) is highly polymorphic and more than 1500 human MHC alleles are known to date. These alleles do not bind to a given peptide with identical affinity. Although MHC alleles are functionally related, it is difficult to quantify the functional variation between them. Three-dimensional structures of known MHC-peptide (MHCp) complexes suggest that specific peptide residues bind selectively to functional pockets in the binding groove. From a set of known MHCp structures we identified 21 critical polymorphic functional residue positions (CPFRP) that significantly reduced functional pocket variability to just 189 among 212 HLA-A alleles. Interestingly 101 HLA-A alleles clustered into 29 clusters such that the six functional pockets formed by the CPFRPs are identical within the cluster.

Section snippets

Abbreviations

    ASA

    accessible surface area

    CPFRP

    critical polymorphic functional residue position

    CTL

    cytotoxic T lymphocyte

    ERP

    essential residue position

    HLA

    human leukocyte antigen

    MHC

    major histocompatibility complex

    MHCp

    MHC peptide

    TCR

    T-cell receptor

Materials and methods

Our recent study on MHCp crystal complexes suggested that residues at 60 positions in the α1, α2 domains are predominantly involved in peptide binding [24]. This is true for a set of MHCp complexes characterized by varying MHC alleles and peptide sequences [24]. These residue positions are called essential residue positions (ERP). The residues at ERPs demonstrated a change in solvent accessibility (ΔASA) of > 0 Å2 upon complex formation in a set of MHCp structures [24]. Among the ERPs, 21

Results

The binding groove between α1 and α2 domains of class I HLA molecules accommodates different types of short peptides. We analyzed the binding grooves of 212 HLA-A alleles for identical functional pockets among them. Using MHCp crystal complexes, we identified 60 ERPs and 21 of these positions are CPFRPs among 212 HLA-A alleles. The frequency of a particular residue at the CPFRPs for the 212 alleles is illustrated in Table 1. The 21 CPFRPs are unevenly distributed in the six functional pockets

Discussion

HLA molecules are highly polymorphic and this is evident from the growth in HLA sequence data at IMGT/HLA [26]. HLA-A and -B are most polymorphic with currently more than 200 and 400 alleles defined by DNA sequence analysis, respectively. HLA molecules are interesting pharmaceutical targets for vaccination and immuno-therapeutics through the design of peptide ligands. The characteristic interaction between peptide and HLA provide the molecular basis for allele-specific recognition of antigenic

Conclusion

The current challenge in synthetic peptide vaccine design is the identification of a minimum number of short antigenic peptides capable of binding to multiple HLA alleles for efficient and broad range immune response. This can be achieved by testing compatibility between each possible peptide against multiple alleles. The binding of a given peptide to a HLA molecule ideally depends on the conformation of the peptide and the cumulative chemical properties of the peptide sequence. Solution

Acknowledgements

The authors wish to thank the anonymous reviewers for their critical comments and intriguing questions.

References (28)

  • K. Falk et al.

    Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules

    Nature

    (1991)
  • P.J. Bjorkman et al.

    Structure of the human class I histocompatibility antigen HLA-A2

    Nature

    (1987)
  • P.J. Bjorkman et al.

    The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens

    Nature

    (1987)
  • G.M. van Bleek et al.

    Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule

    Nature

    (1990)
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