Original contributionCompression of functional space in HLA-A sequence diversity
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)
- et al.
Immunotherapeutic strategies directed at the trimolecular complex
Adv Immunol
(1994) - et al.
MHC molecules as peptide receptors
Curr Opin Immunol
(1993) Chemistry of peptides associated with MHC class I and class II molecules
Curr Opin Immunol
(1995)- et al.
The antigenic identity of peptide-MHC complexesa comparison of the conformations of five viral peptides presented by HLA-A2
Cell
(1993) - et al.
Refined structure of the human histocompatibility antigen HLA-A2 at 26Å resolution
J Mol Biol
(1991) - et al.
The HLA-B14 peptide binding site can accommodate peptides with different combinations of anchor residues
J Biol Chem
(1994) - et al.
The three-dimensional structure of H-2Db at 24 Å resolutionImplications for antigen-determinant selection
Cell
(1994) - et al.
Towards the MHC-peptide combinatorics
Hum Immunol
(2001) - et al.
Structural principles that govern the peptide binding motifs of class I MHC molecules
J Mol Biol
(1998) - et al.
Antigen recognition by class-I restricted T lymphocyte
Annu Rev Immunol
(1989)
Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules
Nature
Structure of the human class I histocompatibility antigen HLA-A2
Nature
The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens
Nature
Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule
Nature
Cited by (22)
Escape of leukemia blasts from HLA-specific CTL pressure in a recipient of HLA one locus-mismatched bone marrow transplantation
2012, Cellular ImmunologyCitation Excerpt :To confirm peptide dependency in CTL recognition, examinations were focused on the difference in the amino acid sequences of the recipient B∗51:01 and the donor B∗52:01. They differed in two amino acids at positions 63 and 67 (Fig. 4A), which constitute peptide binding pockets A and/or B [21,22]. In particular, B-pocket has a critical role in peptide binding to HLA-B∗51:01 molecules [23], and substitution of a single amino acid constituting peptide binding pocket can affect peptide binding [24].
A Novel MHCp Binding Prediction Model
2003, Human ImmunologyDeterminants of resistance to checkpoint inhibitors
2020, International Journal of Molecular SciencesModern developments in short peptide viral vaccine design
2019, Global Virology III: Virology in the 21st CenturyProtein-protein and domain-domain interactions
2018, Protein-Protein and Domain-Domain InteractionsBioinformation discovery: Data to knowledge in biology, Second edition
2018, Bioinformation Discovery: Data to Knowledge in Biology, Second Edition