The Major Histocompatability Complex (hereinafter referred
to as MHC) is vital for the acquired immune system. The MHC region occurs on chromosome
6. The group of proteins, located on the cell surface, recognise foreign
molecules to prevent an immune reaction from occurring, this is specifically
useful in transplant situations. There are two classes of MHC, however this
essay will focus on Class I. Human leukocyte antigens (hereinafter referred to
as HLA) are glycoproteins found on the membranes of the majority of cells in
the body. These proteins are encoded for by numerous gene loci found in the MHC.
Class I MHC’s are heterodimers with non -covalently bonded
alpha and beta II micro-globulin chains polypeptide chains. The alpha chain,
also referred to as the heavy chain, is comprised of three domains, each
roughly 90 amino acids in length and is transmembrane. The first two domains (alpha
I and II) form an eight-stranded beta pleated sheet that provides a basis for
long alpha helices to sit. Alpha I is a continuous and long helix where as in comparison
alpha II is more segmented, these two helices along with the antiparallel beta
sheet forms the base of the peptide binding site form the basis of a groove,
which is 25 Angtstrom in length. The alpha III domain is an immunoglobulin (similarly
to beta 2 micro-globulin) and spans the membrane bilayer.
MHC class 1 molecules use the groove to bind to peptides,
usually between 8 and 10 amino acids in length. This variation in peptide
length is possible due to kinks and bulges in the main chain. Though these
bulges/kinks can vary their ends are fixed which allows for end to end fit within
the groove which remains a certain length (25 angstrom).
MHC’s posses 6 of these pocket like grooves, usually named
A-F. Four of these pockets, B -E, are formed from polymorphic residues, this is
to account for new or mutated pathogens and so occurs from the inheritance of
multiple MHC molecules. With consideration that the peptide binding site is located
within the pockets, the polymorphism allows for the formation of highly
specific grooves which in turn result in a larger variety of peptides being
able to bind. The side chains of the MHC molecules effect the shape, nature and
size of these grooves to increase the specificity.
In each of these pockets there is a conserved water molecule,
which exists to allow for a better fit between the MHC and the peptide.
Furthermore, the water molecules assist in hydrogen bonding networks at both
termini of the polypeptide. There is a large number of hydrogen bonds binding
the MHC to the main chain of the peptide.
Further to water, Class I MCAs have an N- linked
oligosaccharide attached at Asparagine 86. This residue exists in a loop
connecting alpha I to alpha II. The two helices join at roughly 110 degrees.