HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans. MHC Class I molecules such as HLA-A participate in a process that presents short polypeptides to the immune system. These polypeptides are typically 7–11 amino acids in length and originate from proteins being expressed by the cell. There are two classes of polypeptide that can be presented by an HLA protein: those that are supposed to be expressed by the cell (self) and those of foreign derivation (non-self). Under normal conditions cytotoxic T cells, which normally patrol the body in the blood, "read" the peptide presented by the complex. T cells, if functioning properly, only bind to non-self peptides. If binding occurs, a series of events is initiated culminating in cell death via apoptosis. In this manner, the human body eliminates any cells infected by a virus or expressing proteins they shouldn't be (e.g. cancerous cells). For humans, as in most mammalian populations, MHC Class I molecules are extremely variable in their primary structure, and HLA-A is ranked among the genes with the fastest-evolving coding sequence in humans. As of March 2022, there are 7,452 known HLA-A alleles coding for 4,305 active proteins and 375 null proteins.This level of variation on MHC Class I is the primary cause of transplant rejection, as random transplantation between donor and host is unlikely to result in a matching of HLA-A, B or C antigens. Evolutionary biologists also believe that the wide variation in HLAs is a result of a balancing act between conflicting pathogenic pressures. Greater variety of HLAs decreases the probability that the entire population will be wiped out by a single pathogen as certain individuals will be highly resistant to each pathogen. The effect of HLA-A variation on HIV/AIDS progression is discussed below.
HLA-A gene
The HLA-A gene is located on the short arm of chromosome 6 and encodes the larger, α-chain, constituent of HLA-A. Variation of HLA-A α-chain is key to HLA function. This variation promotes genetic diversity in the population. Since each HLA has a different affinity for peptides of certain structures, a greater variety of HLAs means that a greater variety of antigens can be 'presented' on the cell surface, enhancing the likelihood that a subset of the population will be resistant to a given foreign invader. This decreases the likelihood that a single pathogen has the capability to wipe out the entire human population. Each individual can express up to two types of HLA-A, one from each of their parents. Some individuals will inherit the same HLA-A from both parents, decreasing their individual HLA diversity; however, the majority of individuals will receive two different copies of HLA-A. This same pattern follows for all HLA groups. In other words, every single person can only express either one or two of the 2432 known HLA-A alleles.
Alleles All HLAs are assigned a name by the World Health Organization Naming Committee for Factors of the HLA System. This name is organized to provide the most information about the particular allele while keeping the name as short as possible. An HLA name looks something like this: HLA-A*02:01:01:02L All alleles receive at least a four digit classification (HLA-A*02:12). The A signifies which HLA gene the allele belongs to. There are many HLA-A alleles, so that classification by serotype simplifies categorization. The next pair of digits indicates this assignment. For example, HLA-A*02:02 Archived 2013-12-16 at the Wayback Machine, HLA-A*02:04 Archived 2013-12-16 at the Wayback Machine, and HLA-A*02:324 Archived 2013-12-16 at the Wayback Machine are all members of the A2 serotype (designated by the *02 prefix). This group is the primary factor responsible for HLA compatibility. All numbers after this cannot be determined by serotyping and are designated through gene sequencing. The second set of digits indicates what HLA protein is produced. These are assigned in order of discovery and as of December 2013 there are 456 different HLA-A*02 proteins known (assigned names HLA-A*02:01 to HLA-A*02:456). The shortest possible HLA name includes both of these details. Each extension beyond that signifies synonymous mutations within the coding region and mutations outside the coding region. The interpretation of the extensions is covered in greater detail in current HLA naming system.
Protein The protein coded for by the HLA-A gene is 365 amino acids long and weighs roughly 41,000 daltons (Da). It contains 8 exons.
The HLA-A signal peptide is a series of hydrophobic amino acids present at the N-terminus of the protein that directs it to the endoplasmic reticulum where the remaining seven domains are translated. The three α domains form the binding groove that holds a peptide for presentation to CD8+ t-cells. The transmembrane region is the region that is embedded in the phospholipid bilayer surrounding the ER lumen. The HLA-A protein is a single-pass transmembrane protein. In other words, the first four domains of the protein are inside the ER lumen, while the last three domains are present outside the lumen, giving the protein the orientation required for proper function. The last three domains of the protein form a tail of primarily β-sheets that remains in the cell's cytosol.
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