Abstract
Leukocyte cell-surface HLA-I molecules, involved in antigen presentation of peptides to CD8+ T-cells, consist of a heavy chain (HC) non-covalently linked to β2-microglobulin (β2m) (Face-1). The HC amino acid composition varies across all six isoforms of HLA-I, while that of β2m remains the same. Each HLA-allele differs in one or more amino acid sequences on the HC α1 and α2 helices, while several sequences among the three helices are conserved. HCs without β2m (Face-2) are also observed on human cells activated by malignancy, viral transformation, and cytokine or chemokine-mediated inflammation. In the absence of β2m, the monomeric Face-2 exposes immunogenic cryptic sequences on these cells as confirmed by HLA-I monoclonal antibodies (LA45, L31, TFL-006, and TFL-007). Furthermore, such exposure enables dimerization between two Face-2 molecules by SH-linkage, salt linkage, H-bonding, and van der Waal forces. In HLA-B27, the linkage between two heavy chains with cysteines at position of 67 of the amino acid residues was documented. Similarly, several alleles of HLA-A, B, C, E, F and G express cysteine at 67, 101, and 164, and additionally, HLA-G expresses cysteine at position 42. Thus, the monomeric HC (Face-2) can dimerize with another HC of its own allele, as homodimers (Face-3), or with a different HC-allele, as heterodimers (Face-4). The presence of Face-4 is well documented in HLA-F. The post-translational HLA-variants devoid of β2m may expose several cryptic linear and non-linear conformationally altered sequences to generate novel epitopes. The objective of this review, while unequivocally confirming the post-translational variants of HLA-I, is to highlight the scientific and clinical importance of the four faces of HLA and to prompt further research to elucidate their functions and their interaction with non-HLA molecules during inflammation, infection, malignancy and transplantation. Indeed, these HLA faces may constitute novel targets for passive and active specific immunotherapy and vaccines.
Highlights
A protein can be a monomeric single polypeptide chain or two or more such chains
The available literature documents that the cysteine residues exposed in Face-2 may contribute to this interaction resulting in Face-3 molecules
Is slower than many other Human Leukocyte Antigens (HLA)-I molecules, primarily as a result of the specific residues forming the peptide-binding groove. This increase in the time taken for the heavy chain to fold and exit the endoplasmic reticulum (ER) appears to contribute to the accumulation of misfolded ER-resident molecules, which leads to ER stress and the initiation of the unfolded protein response (UPR) [111]
Summary
A protein can be a monomeric single polypeptide chain or two or more such chains (e.g., dimeric or trimeric). A monomeric protein may have secondary structures (α-helix and β-pleated sheets) (Figure 1) and attain a tertiary structure. The amino sequences or epitopes exposed on apolypeptide single polypeptide heavy chain may become cryptic when the protein attainsattains a quaternary structure. If the protein is a glycosylated polypeptide, the exposure of the sugar residues on the protein may differ between the polypeptide, the exposure of the sugar residues on the protein may differ between the single heavy chain version and its di- or trimeric quaternary version. Protein glycosylation single heavy chain version and its di- or trimeric quaternary version. Transferred to aenzymatic steps, a complex oligosaccharide is synthesized in the ER, transferred to a specific receptor sequence on its target protein, and subsequently cropped and remodeled receptor inspecific the ER and. Golgi sequence apparatus.on its target protein, and subsequently cropped and remodeled in the ER and Golgi apparatus
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