Abstract
HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.
Highlights
HLA-E is encoded by the major histocompatibility complex (MHC) locus and belongs to nonclassical MHC class I (MHC Ib) genes
Using enzyme-linked immunosorbent assay (ELISA), it was shown that soluble HLA-E (sHLA-E) was presented in healthy donors, but its level was relatively higher in plasma samples of patients with melanoma [57], neuroblastoma [58], and chronic lymphocytic leukemia [59] on advanced disease stage
Despite the lower affinity to peptides, lower surface expression, and thermal stability of the corresponding protein, allele HLA-endoplasmic reticulum (ER) manifests the clear advantages for individuals subjected to a number of diseases
Summary
HLA-E is encoded by the major histocompatibility complex (MHC) locus and belongs to nonclassical MHC class I (MHC Ib) genes. HLA-E is expressed at the cell surface only after its association with β2-microglobulin and antigenic peptide It differs from classical (MHC Ia) proteins by limited polymorphism and a specific set of presented peptides [1,2]. The leader peptides are cut off by Signal Peptidase and cleaved again by Signal Peptide Peptidase, following by the release of ~14 residue-long signal peptide fragments into the cytosol Therein they are trimmed by proteasome, and transported into endoplasmic reticulum (ER )lumen by transporter associated with antigen processing (TAP) protein [6]. These peptides enter into the HLA-E peptide-binding groove This interaction, as well as association of HLA-E with β2-microglobulin promotes the correct folding of the HLA-E complex and allows it to be expressed at the cell surface [6]. Some of the aforementioned receptors, by being engaged with HLA-E, induce inhibitory signal that protects HLA-E- expressing cells from lysis, whereas others activate lymphocytes, leading to the elimination of target cells
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