Chicken MHC - the 10,000th structure annotated at PDBeThe Protein Data Bank in Europe (PDBe), one of three sites worldwide where PDB data can be deposited, recently annotated its 10,000th PDB entry (see Wellcome Trust press release). This entry (2yf6) is the structure of a chicken MHC, from the B21 haplotype, which is resistant to Marek's disease, a contagious viral disease of commercial importance. The entry is one of a series of chicken MHC structures determined in the laboratory of Professor Susan Lea (University of Oxford) with different peptides bound. These structures will assist scientists in examining the fine detail of how chicken MHCs recognise and bind to peptides and present them to the immune system. In this Quips we will describe the architecture of MHC complexes and how they display peptides to T-cells.
MHC proteins help the immune systemOne of the many ways in which information about an infection can be passed on to the immune system is via the Major Histocompatibility Complex (MHC) proteins. These are molecules on the surface of animal cells that continually sample the protein environment inside the cell and display short fragments of these proteins, typically 8-10 amino acids long, on the cell surface for 'inspection' by T-cells. These then decide if the protein fragment (peptide) displayed is 'self' or foreign and take appropriate action to destroy an infected cell if the peptide is considered to be foreign. When T-cells incorrectly recognise 'self' peptides displayed by MHCs as foreign, autoimmune diseases can occur.
Architecture of MHC complexesTo be able to bind many different peptides, many different MHC proteins are required. The MHC gene locus in mammals is large and highly polymorphic, coding for many different versions of MHC. These also vary considerably between individuals so no two people (except identical twins) will have the same set of MHC proteins. MHCs are membrane-bound molecules. The extracellular portion of MHC proteins consists of three domains, α1, α2 and α3, with α3 located closest to the membrane (red, orange and blue respectively). The protein is associated with a further protein chain, β2 microglobulin (green) as shown in view-1.
Displaying the peptide antigenβ2 microglobulin (which has the same immunoglobulin fold as the α3 domain) stabilises the MHC complex on the cell surface. Together, α3 and β2 microglobulin raise α1 and α2 above the cell membrane where they can present the bound peptide to T-cells. The latter two domains are the most variable and together they form an 8-stranded β-sheet above which lie two α-helices. The displayed peptide is bound between these two domains like a sausage in a hotdog roll (see view-2). Peptides interact with the MHC particularly at their termini, with the central region 'bulging' out of the hotdog roll to be exposed to the T-cell (see view-3).
MHC structures in the PDBMuch is known about mammalian MHCs; indeed the first MHC structure was deposited in the PDB as early as 1987 (1hla - a human MHC). Nowadays, there are several hundred mammalian MHC structures in the archive, but comparatively little is known about non-mammalian MHCs and there are very few such molecules in the PDB.
Chickens use MHCs differently than humansWhereas the mammalian MHC locus is 3.6 megabases, encoding many different MHCs that bind peptides quite specifically, chickens have a much smaller region of their genome encoding MHCs and therefore express far fewer MHC molecules. To avoid falling foul of infection, chicken MHCs have evolved to be 'promiscuous'. While the chicken MHCs are highly similar in fold to their mammalian equivalents, each is capable of displaying a variety of peptides to chicken T-cells (see view-4). You can use the PDBe Pfam browser to explore all structures in the PDB of MHC class I molecules (PF00129), and of β2 microglobulin (PF07654).