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From Proteopedia

Revision as of 02:49, 7 November 2012

Description of Class I MHC

Class I major histocompatibility molecules (MHC-1) are cell surface proteins that signal the presence of intracellular pathogens, such as viruses, to the host’s immune system. When viruses invade a host cell, they use the cell’s machinery to reproduce their nucleic acid and synthesize their proteins. Viral proteins, like cellular proteins, become targets for degradation and recycling, generating small portions of the viral proteins called peptides. Viral peptides of the right size can fit into the binding cleft of MHC-1 molecules, which are then displayed on the surface of the viral-infected cell. Cytotoxic T Lymphocytes (CTL), have receptors for foreign (viral) peptides complexed to MHC-1. When a CTL binds to a viral peptide-MHC-1 complex, the CTL secretes substances that lead to lysis and death of the infected cell, eventually clearing the infection. Thus, MHC-1 molecules function as an important warning system for the presence of intracellular infections. Viruses that develop a way to prevent expression of MHC-1 on the cell surface have a better chance of survival in the host.

History of Class I MHC

The discovery of MHC occurred when tissue allografts were being performed on mice. Inbred strains of mice were developed whose only difference was in graft acceptance and rejection. Further backcrosses provided researchers with recombinant-inbred mice, this led to the discovery of the MHC region on chromosome 17 of the mice. This was how MHC received its name, because these molecules are mediators in graft rejection, they affect whether or not the new tissue is compatible with the tissue already present in the host species. Unless a person receives a skin graft from someone who retains genetically similar MHC molecules, the graft will be rejected because different antigens will be displayed. The immune system will see these different antigens as foreign, and will attack the cells containing the different MHC. It is important to note that Human leukocyte antigen (HLA) is the gene that encodes the cell-surface antigen-presenting proteins, which includes MHC molecules. HLA-A, B, and C all code for the α chain on MHC-I. Since we receive HLA genes from both of our parents, and they are co-dominantly expressed, most of us express 6 different MHC-I on our nucleated cells. The genetic diversity of MHC-I makes it one of the most polygenic and polymorphic protein structures, meaning that each person has a different repertoire of MHC-I, and a variety of MHC-I molecules can be expressed on each nucleated cell.

Stucture of Class I MHC

MHC-1 molecules are composed of two polypeptide or protein chains, an α (a) chain and β-2 microglobulin (b2m). The alpha chain has three external domains designated α1, α2 and α3, a transmembrane region and a short cytoplasmic tail. The α1 and α2 domains interact to form the peptide-binding cleft composed of two α-helical regions and a bottom of antiparallel β strands. β-2 microglobulin associates noncovalently with the α3 domain and stabilizes the complex. Each chain is also being stabilized by a disulfide bond. The binding cleft can fit peptides 8-10 amino acids in length, and both viral and non-viral peptides can be expressed. Peptides are held into the groove by the amino acids that are located at the terminal ends of the peptide, these are called anchor residues. Because the MHC-1 molecule only interacts with the terminal residues, it does not matter what the non-terminal residues are. Therefore, a single MHC-1 molecule can present many different viral peptides, as long as the terminal amino acids are correct for that MHC-1 molecule.

How Class I MHC are Formed

MHC-I molecules are formed in the Endoplasmic Reticulum (ER), and this is where they will first bind to a viral peptide. During the initial folding of the MHC-I molecule, the chaperone proteins calnexin and calreticulin ensure the MHC is folding properly. When the MHC-I molecule is not bound to a peptide, the structure is unstable and will dissociate. Once a short peptide binds to the cleft of the MHC complex, the whole structure is stable and is then transported from the ER to the plasma membrane where the viral peptide can be presented to cytotoxic T cells. The peptide sits in a cleft on the α chain that is formed by two α helices that form a wall, and a β sheet that makes up the floor. This structure is called the peptide binding groove.

Function of Class I MHC

When a virus injects its nucleic acid into a host cell, it uses the cells machinery to replicate its genome and synthesize its proteins. Because the viral proteins are being made within the host cell, the viral proteins can undergo recycling just like host cell proteins. Misfolded proteins are marked for destruction in the cytosol by the addition of a small molecule called, ubiquitin. Once marked by ubiquitin, the protein is sent to the proteasome. Proteosomes are large cylindrical structures with many proteolytic enzymes. In the presence of a virus, the proteasome cleaves proteins into peptides 8-10 residues long twith anchor residues that fit in the peptide binding cleft of MHC-I molecules. The peptides are transported from the cytosol to the lumen of the Endoplasmic Reticulum (ER) via ER membrane proteins called Transporters Associated with Antigen Processing (TAP). MHC-1 molecules are synthesized in ribosomes anchored in the ER membrane. In the ER, the MHC-I molecules first associate with a chaperone protein called calnexin. This helps the very large MHC-I molecule fold correctly into place, and helps it retain a partially folded state in the ER. Calnexin is released b2M binds to the alpha chain on MHC-I. Chaperone proteins, calreticulin and tapasin, stabilize the MHC-1 configuration until a peptide to be loaded into the binding cleft. Once the peptide is bound to MHC-I, TAP, tapasin, and calreticulin, dissociate from the MHC-1:peptide complex. This final, stable MHC-I:peptide complex is targeted to the surface of the cell via the Golgi apparatus.

Effect of HCMV on MHC Class I

When a virus such as HCMV binds to MHC-I, the whole mechanism for alerting the immune system is disrupted. HCMV produces a glycoprotein called US2, through research done by Gewurz et. al. it was found that US2 binds to HLA-2, and this somehow sends MHC-I to the cytosol to be destroyed, instead of to the cell surface. A structural study found that US2 contains an immunoglobulin-like fold (Ig-like fold) that appears to play a role in evading the host’s immune system. An Ig-fold consists of two anti-parallel beta sheets of 110 amino acid residues connected by a disulfide bond. The Ig-like fold in US2 provides an area for extensive binding with the HLA molecule along one of the beta-sheets. Using pulse chase analysis, it was determined that one residue in particular was responsible for the dislocation of MHC-I to the cytoplasm. It has been found that a significant number of organ transplants result in patients infected with HCMV, because of the virus’s ability to establish latency.