MHC- Tightly linked complex of genes encoding for cell surface molecules that are required for antigen presentation and rapid graft rejection.
General organization and inheritance of MHC
Histocompatibility antigens- Rejection of foreign tissues is a result of an immune response to cell surface molecules. This concept is known as histocompatibility antigens.
MHC ENCODES THREE MAJOR CLASSES OF MOLECULES
The MHC complex is a tight collection of genes.
The MHC is referred to as the HLA complex (located on chromosome 6) in humans and H2 complex (chromosome 17 ) in mice
STRUCTURE OF MHC CLASS I
• Class I MHC molecules contain a 45kDa α chain (transmembrane glycoprotein encoded by ABC region of HLA complex) and a 12kDa β2 microglobulin molecule.
• α chain contains 3 external domains (α1, α2 and α3), each contain approx. 90 amino acids
• α chain contains a transmemebrane domain of approx. 25 hydrophobic amino acids followed by a small stretch of charged (hydrophilic) amino acids.
• It also contains a cytoplasmic anchor segment of 30 amino acids
• α1 and α2 interact to form 8 antiparallel β strands spanned by 2 α helices. This forms a deep groove or cleft of approx. 25Å X 10 Å X 11 Å with α helices as sides and β strands as the bottom. This peptide binding cleft is located on the top surface of the MHC molecule.
• It can bind a peptide of 8-10 amino acids
• α 3 and β2 are organized into 2β pleated sheets formed by antiparallel β strands.
• α 3 is highly conserved and contains a sequence that interacts with CD8 molecules of Tc cells
• β2 interacts with α 3 and also with α1 and α2. Interaction of β2 is important for a fully folded conformation.
Assembly of Class I molecules
• β2 microglobulin interact with α3 chain and helps the folding of α chain.
• This structure is stabilized by binding of appropriate peptide to form naïve Class I structure.
• This assembly is transported to the cell surface.
• α 3 and β2 association is important for expression of Class I molecules on cell surface. If no interaction between them,then no active MHC.
STRUCTURE OF MHC CLASS II
• Class II molecules contain a 33kDa αchain (90 amino acids) and a 28kDa βchain (25 amino acids) which are associated by non covalent interactions.
• They are membrane bound glycoproteins with external domain, transmemebrane domain and a cytoplasmic anchor segment.
• There are two external domains: α1 and α2 domain, β1 and β2 domain.
• Peptide binding cleft structure is similar to that in Class I MHC molecules, however class II molecules forms an open pocket instead of a closed pocket (due to lack of conserved residues that bond the terminal residues of short peptides).
