HLA-B*2705
Created by Wai Yam
HLA-B*2705 (PDB ID: 3BP4) from Homo sapiens is a class I major histocompatibility complex (MHC) (10). The human leukocyte antigen (HLA) system is the name of the major histocompatibility complex (MHC) in humans. MHC displays bounded antigen peptides to T-cell receptors (TCRs). This activates the T cells, triggering the immune response (11). Class I consists of a heavy chain bound to a ß2-microglobulin. The heavy chain has two peptide-binding domains, an Immunoglobulin (Ig)-like domain, and a transmembrane region with a cytoplasmic tail (11). The three domains are extracellular and called α-1 and α-2, and α-3 respectively (14). Class I is divided into HLA-A, -B, and –C. The different loci of the human chromosome 6 genes encode the different divisions of the MHC (11). This reveals the class and the divisions are used in the naming. The molecular weight of HLA-B*2705 is 44,692.72 Da and the isoelectric point (pI) is 5.52 (1).
HLA-B*2705 is one variation of HLA-B*27. Another is HLA-B*2709 (PDB ID: 3BP7). HLA-B*2709 differs from HLA-B*2705 by one residue. Instead of Asp-116, it has His-116. HLA-B*27 is one subtype of the HLA-B division. Another is HLA-B*14 and one variation is HLA-B*1402. This differs from HLA-B*2705 by eighteen residues. Three differences include having Ala-11 instead of Ser-11, Trp-97 instead of Asn-97, and Asn-114 instead of His-114. Many variations exist because class I MHC is very polymorphic (10). Also, in both examples, the differences occur near or in the binding groove (8). The ability of the MHC to bind a variety of antigen peptides makes it well-suited for its function in the immune system.
The primary structure is the amino acid sequence of the protein (5). The structure of HLA*B2705 directly correlates with its function. HLA-B*2705 exists physiologically as a heterodimer with an alpha subunit bounded to a beta subunit. This forms the class I MHC (13). It has a self-ligand, cathepsin A signal sequence peptide (pCatA). The mature form of the alpha chain’s sequence has the signaling peptide and the chain with the extracellular domain, transmembrane region, and cytoplasmic tail (13). This chain is the heavy chain of the class I MHC. The alpha subunit has 276 residues (8). It is comprised of the alpha chain’s extracellular membrane and part of the transmembrane region. Residues 1-90 form the α-1 region and residues 91-182 form the α-2 region. These two regions form the two peptide-binding domains. The α-2 region has a disulfide bond connecting residue 101 and 164. Residues 183-274 form the α-3 region, of which only residues 185-271 form the Ig-like domain. The α-3 region has a disulfide bond connecting residue 203 and 259. The mature form of the beta chain’s sequence has the signaling peptide and the chain (13). The chain is the ß2-microglobulin. The beta subunit has 100 residues (8). It is comprised of the end portion of the beta chain. In HLA*B2705, it is residues 277-376 and a disulfide bond connects residue 302 to residue 357. The self-ligand is made of the last nine residues.
Secondary structures are obtained when the polypeptide chains arrange into a characteristic helices or sheets (5). The secondary structure of the alpha subunit is 27% helices and 39% beta-sheets. The subunit also has several 3/10 helices and beta turns. The α-1 and α-2 regions contain alpha-helices and beta strands which contribute to binding of peptides in the peptide-binding domains. The α-3 region contains beta strands only. The secondary structure of the beta subunit is 49% beta sheets and has several beta turns. The self-ligand does not have a secondary structure (8). Tertiary structures are obtained when the polypeptide chains fold and bend to form a compact 3-dimensional shape. This produces the most stable structure possible (5). HLA-B*2705 is found in the extracellular domain which has water. This causes the protein to adopt a compact, globular shape due to the hydrophobic effect. The hydrophobic effect clusters the hydrophobic residues together and the folding places those residues on the inside and the hydrophilic residues outside. This limits the disruption to the hydrogen-bonding of water (5). It also allows the hydrophilic residues to make hydrogen bonds with the water, further stabilizing the structure (5).
HLA-B*2705 has two ligands, pCatA and glycerol and both ligands have binding pockets. pCatA is a self-ligand that is common to HLA-B*2705, -B*2709, and -B*1402. It can be used to see how the different variations interact with it (8). It also stabilizes the heterodimer. Two important residues in the binding pocket of pCatA is Thr-24 and Tyr-171 and they both are found in the alpha subunit. The ligand, glycerol (GOL), and the reservoir solution are mixed together to produce the cryoprotectant solution. The crystallization of the protein is soaked in that solution for 20-30 seconds (8). With the correct peptide, water-mediated contact might exist between the peptide and the HLA-B*2705 at Arg-62 and Glu-163, increasing its stability (8).
HLA-B*27 is linked to the occurrence of several diseases. Notably, it has been associated with ankylosing spondylitis (AS). Its exact role is unclear but many hypotheses exist (10). AS is an inflammatory disease affecting the joints of the spine and pelvis and results in fixed rigidity of the spine (2). More than 90% of individuals with the disease express HLA-B*27 (10). The most common variation across broad ethnic and geographic boundaries is HLA-B*2705. On the other hand, HLA-B*2709 does not predispose for AS (7). The two variations again differ at the one residue, residue 116. HLA-B*2706 has been argued in both ways and it differs from HLA-B*2705 at multiple residues. It is possible that HLA-B*27 itself, or in complex with a peptide, serve as a target of an autoimmune response (10).
YF1*7.1 (PDB ID: 3p73) from Gallus gallus is a heterodimer with an alpha subunit and a beta subunit (9). Like HLA-B*2705, the alpha subunit is the heavy chain and the beta subunit is a ß2-microglobulin (3).The heterodimer forms a class I MHC. In chickens, class I MHC is divided in YF1 and YF2 instead of HLA-A, -B, and –C (3). The Dali server finds proteins with similar tertiary structures to the protein of interest and produces Z-scores. Z-scores above 2 indicate the protein have similar folds and have significant similarities (6). Position-Specific-Iterated Basic Local Alignment Search Tool (PSI-BLAST) finds proteins with similar primary structure to the protein of interest and assigns E values to them. An E value of less than 0.05 indicates a significant match while an E value of 0.0 indicates the protein of interest have an identical primary structure to the similar protein (12). The results of Dali (Z=27.6) and PSI-BLAST (E=9e-102) searches show that YF1*7.1 has both primary and tertiary similarities to HLA-B*2705 (6 & 12).
The primary and tertiary structure is similiar since both proteins are class I MHC and have similiar functions. Unlike HLA-B*2705, YF1*7.1 does not require a ligand to stabilize the cell surface-expressed heterodimer (3). The secondary structure of the alpha subunit is 27% helices and 41% beta sheets and the beta subunit is 47% beta sheet. The alpha subunit consists of several 3/10 helices and beta turns while the beta subunit consists of several beta turns only (9). The percentage of beta strands for the YF*7.1 and alpha helices or the lack there of is about the same as HLA-B*2705. In addition, the alpha subunit has alpha helices and beta strands in the first-third and second-third of the sequence before switching to beta strands only. Two loops in the α-1 domain differ in location and conformation between HLA-B*2705 and YF1*7.1. A salt bridge exists between the loop with Asp-14 and B2-microglobulin in chickens but not in humans. A salt bridge exists between Arg-14 and the loop with Asp-39 in humans but not in chickens (9). Lastly, YF1*7.1 can interact with hydrophobic ligands, expanding the ligand repertoire while minimizing the amount of class I MHC (9).