The MHC Flashcards
αβγδεμκλ
MHC
Aka HLA
cell surface glycoptroteins
Function = to present peptides to T cells. A single MHC can bind a broad range of peptides composed of different aa combinations.
Two types: class I and II. V similar 3D structures but important biochemical differences.
MHC Class I
Structure?
Peptide binding groove?
Transmembrane heavy (α) chain (45kD) non-covalently linked to a β2-microglobulin (12kD, not transmembrane). Heavy chain has 3 extracellular domains α1, α2, α3.
Peptide binding groove
- Formed by heavy chain membrane distal domains (α1 and α2)
- pockets at each end interact with the amino and carboxy terminus of the peptide- places restrictions on length.
- Peptides up to 8-9aa in length bind in an extended conformation. Slightly longer (10aa) can bind if they bend in the middle
- base consists of β pleated sheet, 2α helices form the sides
MHC Class II
Structure?
Peptide binding groove?
Two similar sized transmembrane chains: α (33kD) and β (30kD).
Peptide binding groove:
- formed by α1 and β1 domains
- supported by membrane-proximal α2 and β2
- open ended
- can bind peptides 13-25 aa in an extended conformation
MHC diversity is due to
Polygeny
Polymorphism
MHC polygeny
Polygeny refers to the expression of multiple different loci encoding class I and II genes. 3 class I isotypes: HLA-A, HLA-B, HLA-C 3 class II isotypes: HLA-DP, HLA-DQ, HLA-DR
MHC polymorphism
Polymorphism= existence of many alternative forms of the same gene within the human pop.
MHC are among most polymorphic genes known.
- large numbers of alleles, sometimes >250 at each locus
- alleles differ by 1-50aa, and are often expressed at significant frequency (>1%) in pop
Extensive allelic polymorphism is thought to be pathogen driven, & is unique to the MHC.
MHC inheritance
MHC loci are closely linked genetically, in ~97% cases inherited as haplotypes (sets of alleles).
Alleles are co-dominantly expressed:
- both maternal & paternal haplotypes expressed together on same cell
- in outbred pops, polymorphism at each loci makes it virtually impossible that 2 individuals will express the same combination of MHC alleles -> + as heterozygotes can present more peptides than homozygotes.
Peptide presentation
Each MHC molecule binds a different characteristic set of peptides.
Anchor residues= conserved amino acids at certain positions of the peptide to be bound that make specific contacts with pockets in the binding groove. Together determine the peptide-binding motif for that particular MHC.
AA at non-anchor residues may vary considerably- accounts for the diversity of peptides presented by a single MHC.
MHC class I antigen processing pathway
Present peptides from within the cell to CD8 cytotoxic T cells.
- cytosolic proteins are continuously degraded into peptides, predominantly by the proteasomae
- TAP (transporter associated with antigen processing) moves peptides from cytosol -> ER.
- Peptides of suitable length & sequence loaded onto partially folded class I molecules. Assisted by chaperone proteins
- Fully loaded MHC peptide complexes are released from the chaperones, pass -> golgi, then follow secretory pathway -> cell surface.
MHC class II antigen processing pathway
Present extracellular peptides to CD4 T cells.
Class II molecules have to pass through ER during their biosynthesis. To prevent binding peptides in the ER, class II α/β chains associate with invariant chain Ii:
- blocks peptide binding groove
- acts as a folding chaperone
- targets class II/Ii complexes to the endocytic pathway.
Class II/Ii complexes pass from ER through golgi.
In the endocytotic pathway Ii is partially removed, leaving a small peptide called CLIP in the peptide binding groove.
Antigens taken up into cell by exocytosis are degraded into peptides by proteases.
Within MIIC compartments (peptide loading compartments), CLIP peptide is removed, antigen derived peptides are loaded onto empty class II. MHC class II/ peptide complexes then transported to cell surface/
