Let’s look at the structure of the
protein encoded by these genes.
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.
It is just the α1 and the α2-domains of the
α-chain of MHC Class I that is polymorphic.
The β-chain as we’ve already mentioned, doesn’t vary at all
from one individual to another in the MHC Class I molecules.
It has a specific name, its
And it doesn’t function in peptide
binding but its function is to maintain
the correct structural conformation of the MHC Class I molecule.
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.
Here we can see, looking down onto the surface
of the MHC Class I molecule, the two α-helices.
Underlying those two α-helices
is the β-sheet floor.
And the peptide antigen sits between those two α-helices
on the β-sheet floor as we can see in this diagram.
The polymorphic residues in MHC Class I are
indicated by these yellow squares in the diagram.
And as you can see, the polymorphic residues occur
both in the α-helices and on the β-sheet floor.
And this is what determines which peptides
will bind in the peptide binding group.
So this is another representation
of the structure of MHC Class I.
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.
And then the transmembrane region of the α-chain
holding this molecule in the cell membrane.
And at the tip we have the peptide binding groove with the
peptide sitting between the two α-helices on the β-sheet floor.
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.
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.
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.
This is a representation from the crystal structure
of peptides sitting in the MHC binding groove.
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.
And these MHC Class I molecules bind
peptides that are eight to nine amino acids long.
In contrast, MHC Class II molecules,
and we see here an example of HLA-DR1.
They tend to bind longer peptides, typically around
about 15 amino acids in length, they can be longer.
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.
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.
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.
So each MHC, let’s say HLA-A2, doesn’t
bind just a single peptide sequence.
It can bind multiple
And the same is true
for the MHC Class II.
So here we have an example of
an MHC Class II binding peptide.
So it will have various amino
acids and at certain positions, it
will need to have amino acids with particular characteristics.
But it doesn’t care what the amino
acids are at the other positions.
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.
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.
Other amino acids would not fit into the peptide
binding groove of this particular MHC variant.
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.
But as long as those two criteria are met, the other
amino acids can really be any out of the 20 amino acids.
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.