M H C class I molecules

The first hints about the MHC class I structure were gained in 1981 w h e n c la ss I m o le c u le s w e re p u r i f ie d by a ff i n i ty c h ro m a to g ra p h y and su b jected to am ino acid sequence analysis (Coligan, 1981). The heavy chain comprises five distinct structural domains: 3 distinct, globular dom ains o f - 1 0 0 amino acids each w hich are exposed on the outside o f the cell, a transm em brane

Figure 1.2 Schematic representation of the structures of MHC class I molecules, “classical” MHC class II molecules and HLA- DM (hypothetical). Class I “cla ssica l” class II- m o le c u le s DM H S' a i t t 2 a i l u m e n a t r a n s ­ m e m b r a n e d o m a i n c y t o ­ p l a s mi c t ai l c N - l i n k e d o l i g o s a c c h a r i d e

Each heterodimeric m o lec u le consists o f four globular domains that are anchored in the lipid bilayer by at least one transmembrane region. The membrane-proximal domains o f all MHC class I and class II molecules are hom ologous to Ig domains. The membrane-distal domains form the peptide binding groove in the case o f MHC class I molecules and “classical “ MHC class II molecules. The “unconventional” HLA-DM does not seem to have a

functional peptide binding groove. In contrast to other MHC class II

molecules, the a j- d o m a in o f DM has a disulphide bridge. The |3i-domain of DM has fiv e cysteine residues, four of which are potentially involved in disulphide bridge formation, and one free one.

region of approximately 25 amino acids and a cytoplasm ic dom ain comprising 30 - 40 amino acids, each encoded by a separate exon. The three extracellular domains are referred to as- a l , a2 and a 3. The detailed structure of an MHC class I m olecule was revealed in 1987 w h e n th e X - r a y c r y s t a l l o g r a p h i c s t r u c t u r e o f th e extracellular domains o f HLA-A2 was p ublished (B jorkm an et al., 1987a; B jorkm an et al., 1987b) (figure 1.3A). The three heavy- chain external dom ains and p 2 -m icro g lo b u lin fo rm two p airs o f interacting domains: a m em b ran e-p ro x im al p a ir m ad e up o f the a s dom ain and P 2 -m ic ro g lo b u lin an d a m e m b r a n e - d is ta l p a ir consisting o f the a i and a 2 dom ains, a s and p2 m are b o th

com posed o f two an tip arallel p leated p-sheets, c o n n e c te d by a disulphide bridge. This tertiary structure is very sim ilar to the one o f the immunoglobulin constant region. The a i and a 2 domains do not show homology to any known proteins but are nearly identical to one another.

The antigen binding site is located on the top surface o f the M H C heterodim er and is characterised by a deep cleft betw een two long a -h e lic es derived from the a i and a 2 dom ains (figure 1.4). T he floor of the groove is formed by P-strands from the same dom ains. The dimensions of the groove are 2.5 nm long, 1 nm wide and 1.1 nm deep which is sufficient to accom m odate peptides betw een 8- 20 amino acids length. In the in itial crystal stru ctu re e le ctro n density w hich could no t be a cco u n ted for by the am ino acid s e q u en c e o f the H L A -m o le c u le w as o b s e r v e d in the c le f t, presumably representing such bound antigens.

Figure 1.3 A

The structures of MHC class I and class II molecules B peptide-binding cleft i | \ \ \ P2 ' microglobulin 1^ I peptide-binding cleft

The crystal structures of HLA-A2 (A) and HLA-DRl (B) are shown in comparison. The left panels show computer graphic representations and the right panels ribbon diagrams. The comparison demonstrates that the two classes of MHC molecules have very similar structures although the subunit composition of the two molecules is different. Images were adopted from Immunobiology. The Immune System in Health and Disease.

F ig u re 1.4 Comparison of the MHC class I and class II peptide binding grooves A B peptide-binding ' / / cleft / / peptide-binding c l e f t / y (3 stieet a helix «2

A The M H C cla ss I peptide bind in g gro o v e . B The M HC cla ss II peptide

b in d in g g r o o v e . Upper panel: s c h e m a tic representation o f the M H C c la s s I and c la s s II peptide binding c le fts. M id d le panel: ribbon diagram m e. L o w e r panel: sp a c e -fillin g diagramme. The peptide is show n in red.

W hereas in the case o f M HC class I m o le c u le s the peptide is tightly bound at either end o f the gr oo ve , in the case o f M HC class II m o le c u le s the peptide can protrude out o f the gro o v e . For both c la s s e s o f m o le c u le s the peptide

binds in an extended c onform ation. Im ages taken from I m m u n o b i o l o g y . The

I mmune S y s t e m in He a l th a n d D i s e a s e . Paul Travers and Charles A. Janeay,