There are two primary classes of major histocompatibility complex (MHC) molecules, class I and MHC class II. MHC class I molecules are found on every nucleated cell of the body (and thus not on erythrocytes). Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.
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Function
MHC class I molecules bind peptides mainly generated from degradation of cytosolic proteins. The MHC-I-peptide complex is then inserted into the plasma membrane of the cell. The peptide is bound to the extracellular part of the MHC-I molecule. The function of the MHC-I is thus to display to the environment, specifically T cells of the immune system, what kind of proteins are being made within the cell.
A normal cell will display normal peptides on its MHC-I, and be left alone by the T cells. Upon a viral infection of a cell, some viral proteins will be degraded in the cytosol. Subsequently, viral peptides will be presented on its MHC-I molecules and the cell will be recognized and killed by T cells. Viral, or other foreign peptides, presented on a cell's MHC-I molecules will in other words flag the cell for destruction.
Structure
MHC class I molecule consists of two polypeptide chains, α and β2-microglobulin. The two chains are associated noncovalently. Only the α chain is polymorphic and encoded by MHC gene, while the β2-microglobulin is not polymorphic and encoded by other gene. The α3 domain is transmembrane where CD8 binds. The α1 and α2 domains fold to make up a groove for peptides to bind. MHC class I molecule binds peptides that are 8-10 amino acid in length (Parham 87).
Production
The peptides are mainly generated in the cytosol by the proteasome. The proteasome is a macromolecule that consists of 28 subunits, of which half affect proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER.
Translocation
The peptide translocation from the cytosol into the lumen of the ER is accomplished by the transporter associated with antigen processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under ATP consumption into the lumen of the ER. The MHC class I molecule is then in turn loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex consisting of TAP, tapasin, calreticulin, calnexin, and ERP57.
Once the peptide is loaded onto the MHC class I molecule, it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of the protein, followed by extensive changes to the N-glycans in the Golgi apparatus. The N-glycans mature fully before they reach the cell surface.
Peptide removal
Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum are removed from the ER via the sec61 channel into the cytosol,[1][2] where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule.
For example, an interaction of sec61 with bovine albumin has been observed.[3]
Effect of viruses
MHC class I molecules are loaded with proteins generated in the cytosol. As viruses infect a cell by entering its cytoplasm, this cytosolic, MHC class I-dependent pathway of antigen presentation is the primary way for a virus-infected cell to signal T cells.
MHC class I molecules generally interact with CD8+ ("cytotoxic") T cells (CTLs).[4]
The fate of the virus-infected cell is almost always apoptosis initiated by the CTL, effectively reducing the risk of infecting neighboring cells.
Genes and isotypes
Additional images
 TCR-MHC bindings |
References
- ^ Koopmann JO, Albring J, Hüter E, et al. (July 2000). "Export of antigenic peptides from the endoplasmic reticulum intersects with retrograde protein translocation through the Sec61p channel". Immunity 13 (1): 117–27. PMID 10933400. http://linkinghub.elsevier.com/retrieve/pii/S1074-7613(00)00013-3.
- ^ Albring J, Koopmann JO, Hämmerling GJ, Momburg F (January 2004). "Retrotranslocation of MHC class I heavy chain from the endoplasmic reticulum to the cytosol is dependent on ATP supply to the ER lumen". Mol. Immunol. 40 (10): 733–41. PMID 14644099. http://linkinghub.elsevier.com/retrieve/pii/S0161589003002530.
- ^ Imai J, Hasegawa H, Maruya M, Koyasu S, Yahara I (January 2005). "Exogenous antigens are processed through the endoplasmic reticulum-associated degradation (ERAD) in cross-presentation by dendritic cells". Int. Immunol. 17 (1): 45–53. doi:. PMID 15546887. http://intimm.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15546887.
- ^ "Medmicro Chapter 1b". http://gsbs.utmb.edu/microbook/ch001b.htm. Retrieved on 2009-01-21.
External links
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