Mhc Molecule

Major histocompatibility complex The major histocompatibility complex (MHC) is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproductive success. The proteins encoded by the MHC are expressed on the surface of cells in all jawed vertebrates, and display both self antigens (peptide fragments from the cell itself) and nonself antigens (e.g. fragments of invading microorganisms) to a type of white blood cell called a T cell that has the capacity to kill or co-ordinate the killing of pathogens, infected or malfunctioning cells.

Classification In humans, the 3.6-Mb (3 600 000 base pairs) MHC region on chromosome 6 contains 140 genes between flanking genetic markers MOG and COL11A2.[1] About half have known immunological functions (see human leukocyte antigen). The same markers in the marsupial Monodelphis domestica (gray short-tailed opossum) span 3.95 Mb and contain 114 genes, 87 shared with humans.[2]

Subgroups The MHC region is divided into three subgroups called MHC class I, MHC class II, and MHC class III. Name

Function

Expression

MHC class I

All nucleated cells. MHC class I proteins Encodes heterodimeric peptide-binding proteins, as contain an a chain & b2-micro-globulin b well as antigen-processing molecules such as TAP and chain. They present antigen fragments to Tapasin. cytotoxic T-cells cells and will bind to CD8 on cytotoxic T-cells.

MHC class II

Encodes heterodimeric peptide-binding proteins and On antigen-presenting cells MHC class II proteins that modulate peptide loading onto MHC proteins contain a & b chains and they present class II proteins in the lysosomal compartment such as antigen fragments to T-helper cells by binding MHC II DM, MHC II DQ, MHC II DR, and MHC II to the CD4 receptor on the T-helper cells. DP.

Encodes for other immune components, such as MHC complement components (e.g., C2, C4, factor B) and class III Variable (see below) some that encode cytokines (e.g., TNF-α) and also region hsp. Class III has a very different function than do class I and class II, but it has a locus between the other two (on chromosome 6 in humans), so they are frequently discussed together.

MHC I Molecules The basic structure of an MHC I molecule is show by the diagram to the right. It is comprised of two polypeptide chains. The first is long and consists of an intracellular domain, a transmembrane domain, and three extracellular domains. The second polypeptide chain is short and consists of one domain.

CLASS I MOLECULES Class I molecules are composed of two polypeptide chains; one encoded by the BCA region and another (ß2-microglobulin) that is encoded elsewhere. The MHC-encoded polypeptide is about 350 amino acids long and glycosylated, giving a total molecular weight of about 45 kDa. This polypeptide folds into three separate domains called alpha-1, alpha-2 and alpha-3. ß2-microglobulin is a 12 kDa polypeptide that is non-covalently associated with the alpha-3 domain. Between the alpha-1 and alpha-2 domains lies a region bounded by a beta-pleated sheet on the bottom and two alpha helices on the sides. This region is capable of binding (via non-covalent interactions) a small peptide of about 10 amino acids. This small peptide is "presented" to a T-cell and defines the antigen "epitope" that the T-cell recognizes (see below). The following images illustrate the structure of the class I MHC as seen schematically, and three dimensionally from the side and from the top (T-cell perspective). The MHCencoded polypeptide is shown in blue, the ß2-microglobulin is green and the peptide antigen is red. How a peptide from a protein synthesized in a cell winds up bound to an MHC I molecule on the surface of the cell. These are the steps: • • • • • • •

A protein (such as a viral protein) is marked for destruction by binding to ubiquitin The protein is degraded to peptides by a proteasome. For the MHC I molecule the peptides and 8 to 11 amino acids in length. The peptides are transferred into the rough ER via a TAP transporter. Meanwhile, an MHC I molecule is synthesized and placed in the membrane of the rough ER. A peptide binds in the groove in an MHC I molecule. The combination moves through the Golgi apparatus and into a secretion vesicle. Exocytosis of the secretion vesicle places the MHC I molecule with its peptide on the surface of the cell.

•

The peptide and MHC I molecule are now in position to be recognized by a T cell receptor on a T cell. Is this a CD4+ or CD+8 T cell?

MHC II Molecules The MHC II molecule also has two polypeptide chains. But here each polypeptide chain consists of an intracellular domain, a transmembrane domain, and two extracellular domains. Nonetheless, a similar pocket for binding a peptide is found at the top. The domain structure is similar to the MHC I molecule.

CLASS II MOLECULES Class II molecules are composed of two polypeptide chains, both encoded by the D region. These polypeptides (alpha and beta) are about 230 and 240 amino acids long, respectively, and are glycosylated, giving molecular weights of about 33 kDa and 28 kDa. These polypeptides fold into two separate domains; alpha-1 and alpha-2 for the alpha polypeptide, and beta-1 and beta-2 for the beta

polypeptide. Between the alpha-1 and beta-1 domains lies a region very similar to that seen on the class I molecule. This region, bounded by a beta-pleated sheet on the bottom and two alpha helices on the sides, is capable of binding (via non-covalent interactions) a small peptide of about 10 amino acids. This small peptide is "presented" to a T-cell and defines the antigen "epitope" that the T-cell recognizes (see below). The following images illustrate the structure of the class II MHC as seen schematically, and three dimensionally from the side and from the top (T-cell perspective). The MHCencoded polypeptides are shown in yellow and green, while the peptide antigen is shown in red. The big difference, however, is that a peptide from a phagocytized protein is bound the the MHC II molecule on the surface of the cell. The sequence is: • • • • • •

A pathogen is phagocytized, thereby winding up in a phagocytic vesicle. A lysosome with proteases fuses with the phagocytic vesicle, and the proteases digest the proteins into peptides. Meanwhile the MHC II molecule is synthesized in the rough ER. A vesicle with the MHC II molecule now fuses with the vesicle containing the peptides, and a peptide bind to each MHC II molecule. Exocytosis again places the MHC molecule and its peptide on the surface of the cell. The peptide and MHC II molecule are now in position to be recognized by a T cell receptor on a T cell. Is this a CD4+ or CD+8 T cell?

HLA genes Main article: Human leukocyte antigen

The best-known genes in the MHC region are the subset that encodes cell-surface antigen-presenting proteins. In humans, these genes are referred to as human leukocyte antigen (HLA) genes, although people often use the abbreviation MHC to refer to HLA gene products. To clarify the usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule; however this convention is not consistently adhered to. The most intensely-studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the MHC is divided into three regions: Class I, II, and III. The A, B, and C genes belong to MHC class I, whereas the six D genes belong to class II. Besides being scrutinized by immunologists for its pivotal role in the immune system, the MHC has also attracted the attention of many evolutionary biologists, due to the high levels of allelic diversity found within many of its genes. Indeed, much theory has been devoted to explaining why this particular region of the genome harbors so much diversity, especially in light of its immunological importance.