Lecture 10 - Antigen Processing and Presentation Flashcards
Which part of MHC is polymorphic?
The binding pocket
How do binding pockets differ?
Whether they are hydrophobic, carry a negative charge, are acid, etc.
Contingent upon which amino acids make up groove
How are peptides specific to a particular MHC?
Peptides binding one MHC share anchor residues
EG: HLA-A2 - Position 2 = leucine, position 9 = valine
Which parts of a peptide interact with TCR?
Non-anchor residues
How do peptides bind into MHC?
Using anchor side chains
Must all pockets be perfectly filled for peptide to bind MHC?
No
What does alpha3 bind?
CD8
What does Beta2 of MHCII bind?
CD4
Difference in shape between MHCI and II
MHCI is more closed. Peptide termini aren’t exposed
MHCII is more open. Peptide termini are exposed
Why are peptide termini bound to MHCI not exposed?
N- and C-termini need to form conserved hydrogen bonds in order to bind,
This also restricts peptide length
Which MHC can bind multiple peptides with the same epitope?
MHCII
Peptides with the same core sequence
How can MHCII bind multiple peptides with the same epitope?
Peptides have same core sequence, but have been differently processed. Therefore have different sequences either side of core sequence.
MHCII can have exposed peptide termini
What are anchor residues?
Residues that bind pockets
Limit on MHCII structure
Need to have conserved structures to bind invariant chain
Who is polygeny good for?
Individual
Who is polymorphism good for?
Population
What is antigen processing?
Intracellular proteolytic generation of MHC-binding peptides
Can MHC bind self peptides?
Yes. Very frequently.
MHCII processing pathway 1) 2) 3) 4)
1) Internalisation of protein
2) Protein degraded to small peptides in late endosome by acid.
3) MHCII bound to invariant chain leaves ER, binds to endosome. Forms MIIC compartment
4) MHCII/antigen complex, expressed on surface
Which proteins are expressed on MHCII?
Proteins in endosomal/lysosomal network. Many self antigens
Why do hapens need a carrier?
Too small to be able to fit into MHC without carrier
Can’e elicit a T cell response
Why does MHCII have invariant chain?
So that MHCII doesn’t bind peptides in the ER.
Very large number of self antigens in ER, don’t want these expressed on MHC
Roles of invariant chain
1) Prevent binding of unwanted proteins to MHCII
2) Target MHCII to endosomal network
Most efficient way for antigens to be internalised
Receptor mediated endocytosis (BCR, FcR)
Where does invariant chain bind MHCII?
ER
Murine HLA-DM
H-2M
Muman H-2M
HLA-DM
What is HLA-DM?
Removes CLIP from MHCII in MIIC
What removes CLIP from MHCII?
HLA-DM
Where does CLIP come from?
Degradation of invariant chain
Some is left in the MHC binding groove
Where is invariant chain degraded?
MIIC
Very important proteins in MHCI pathway
1)
2)
1) Proteosome
2) Transporter associated with Antigen Processing (TAP)
TAP 1) 2) 3) 4)
1) Heterodimeric protein (TAP1/TAP2)
2) ATP-binding cassette superfamily
3) Transports peptides from cytosol into ER (8-16aa in length)
4) Upregulated by gamma-interferon
Proteosome
Large, multi-subuunit protein complex
How does the proteosome alter function in infection?
1) Altered by IFNg, by replacing subunits with alternate subunits
2) Alternate protein subunits involved in antigen processing: Lmp2, Lmp7, MECL1, PA28
Where do MHCI stay until binding peptide?
ER
Which MHC does invariant chain bind?
MHCII
