Structure of Major Histocompatibility Complex – Antigen Processing and Presentation

00:01 Let’s look at the structure of the protein encoded by these genes.

00:06 So for the α-chain of MHC Class I, the chain is folded into three different domains - an α1-domain, an α2-domain, and then sitting next to the membrane the α3-domain.

00:22 It is just the α1 and the α2-domains of the α-chain of MHC Class I that is polymorphic.

00:31 The β-chain as we’ve already mentioned, doesn’t vary at all from one individual to another in the MHC Class I molecules.

00:40 It has a specific name, its called β2-microglobulin.

00:44 And it doesn’t function in peptide binding but its function is to maintain the correct structural conformation of the MHC Class I molecule.

00:56 And at the tip of this molecule are the two α-helices and the β-sheet floor that form the peptide binding groove where the peptide antigen sits.

01:08 Here we can see, looking down onto the surface of the MHC Class I molecule, the two α-helices.

01:17 Underlying those two α-helices is the β-sheet floor.

01:21 And the peptide antigen sits between those two α-helices on the β-sheet floor as we can see in this diagram.

01:34 The polymorphic residues in MHC Class I are indicated by these yellow squares in the diagram.

01:41 And as you can see, the polymorphic residues occur both in the α-helices and on the β-sheet floor.

01:49 And this is what determines which peptides will bind in the peptide binding group.

01:54 So this is another representation of the structure of MHC Class I.

01:59 You can see the non-variable β2-microglobulin and the three domain structure of the α-chain folded into the α1, α2 and α3-domains.

02:10 And then the transmembrane region of the α-chain holding this molecule in the cell membrane.

02:17 And at the tip we have the peptide binding groove with the peptide sitting between the two α-helices on the β-sheet floor.

02:28 The CD8 molecule that binds to the non-polymorphic region of MHC Class I α-chain needs to recognize areas that do not vary and you can see indicated on this slide the exact location of that CD8 binding site.

02:49 Turning now to the MHC Class II structure again, the α-chain and the β-chain folded into two domains each, an α1-domain and α2-domain for the α-chain, β1-domain, β2-domain for the β-chain, with the peptide binding groove at the tip, again between the two α-helices and sitting on the β-sheet floor.

03:14 Again, this MHC molecule needs to be recognized by CD4 on the surface of T-cells and the CD4 binding site is associated with the non-polymorphic region of the MHC Class II molecule as indicated.

03:32 This is a representation from the crystal structure of peptides sitting in the MHC binding groove.

03:41 On the left you can see an example of an MHC Class I molecule, it just happens to be HLA-A2, it really doesn’t matter which one it is but it’s HLA-A2 as an example of an MHC Class I molecule.

03:56 And these MHC Class I molecules bind peptides that are eight to nine amino acids long.

04:07 In contrast, MHC Class II molecules, and we see here an example of HLA-DR1.

04:14 They tend to bind longer peptides, typically around about 15 amino acids in length, they can be longer.

04:21 And the reason that the Class II binds longer peptides than Class I is that the peptide binding groove in MHC Class I is actually closed at both ends.

04:31 So it can’t accommodate a longer peptide, whereas the Class II binding groove is open at both ends and therefore longer peptides can be accommodated.

04:41 So unlike antibody recognition of antigen, which is very highly specific for a single structure on a single antigen; and T-cell receptor recognition of peptide MHC which is highly specific for a single peptide sequence within a given MHC molecule, the peptides that bind to MHC molecules can actually vary enormously.

05:04 So each MHC, let’s say HLA-A2, doesn’t bind just a single peptide sequence.

05:11 It can bind multiple peptide sequences.

05:14 And the same is true for the MHC Class II.

05:16 So here we have an example of an MHC Class II binding peptide.

05:20 So it will have various amino acids and at certain positions, it will need to have amino acids with particular characteristics.

05:30 But it doesn’t care what the amino acids are at the other positions.

05:33 So as long as there are certain amino acids at certain locations that can fit into pockets in the floor of the peptide binding groove, then the other amino acids can vary.

05:45 So for example, the anchor residues that are required in this particular peptide would be at this location indicated, you need to have either a tyrosine or a phenylalanine.

06:00 Other amino acids would not fit into the peptide binding groove of this particular MHC variant.

06:07 And there’s another position where you need a particular amino acid to be present, and that can be a leucine or an isoleucine or a methionine or a valine.

06:16 But as long as those two criteria are met, the other amino acids can really be any out of the 20 amino acids.

06:23 And that means that for a given MHC molecule, let’s say HLA-DR6, you can bind that molecule… HLA-DR6 can bind maybe hundreds of different peptides.