Introduction to the MHC (structure and function) Flashcards
what is MHC?
peptide receptors
what size peptide does MHC-I accommodate?
8-9 amino acid peptides
what size peptides does MHC-II accommodate?
13-25 amino acid peptides
what is the stability of MHC?
both MHC are instable when a peptide is not bound
what type of cell is MHC-II always present on?
antigen presenting cells always have MHC-II on their surface
what type of MHC do B cells express?
equally express MHC-I and MHC-II
what type of MHC do T cells express?
primarily MHC-I and sometimes MHC-II
what type of MHC do macrophages express?
Both MHC-I and MHC-II but more MHC-I
what type of MHC do dendritic cells express?
equally strong expression of both MHC-I and MHC-II
what type of MHC do epithelial cells of the thymus express?
MHC-I at low levels and MHC-II at high levels
what type of cells express low levels of MHC-I but no MHC-II?
hepatocytes
Kidney cells
Brain cells
what type of MHC do neutrophils express?
MHC-I strongly
what type of MHC do red blood cells express?
No MHC
what are the common domains of MHC-I and MHC-II protein structure?
- Membrane-distal domains
- Membrane-proximal domains (Ig fold structure)
- Transmembrane segment
- Cytoplasmia tail
where is the peptide binding groove found within both MHC-I and MHC-II?
in the membrane distal domains
what are the membrane distal domains of MHC-I?
Alpha 1 and Alpha 2 subunits
what are the membrane-proximal domains of MHC-I?
Alpha 3 and Beta 2 microglobulin subunits
what are the membrane distal domains of MHC-II?
Beta 1 and Alpha 1
what are the membrane proximal domains of MHC-II?
Alpha 2 and Beta 2
where are most of the polymorphisms in MHC-II found?
In the beta 1 subunit
what is the structure of the MHC-I peptide binding groove?
Found between the alpha 1 and alpha 2 domains, which are connected via protein beta sheets
what is the structure of the MHC-II peptide binding groove?
Between the alpha 1 domains and beta 1 domain and is also connected via beta sheets
what mediates peptide binding to MHC?
anchor residues
what can knock a protein out of the MHC binding groove?
Can be released (elluted) by acidic buffers (pH2-3)
- this makes the MHC very unstable
how are proteins eluted from the same MHC comparable?
Peptides eluted from the same MHC molecules show similar patterns in peptide sequence
- they have distinct amino acid patterns
what is the different when short and long peptides bind in the MHC peptide binding groove?
Long peptides bulge when they bind
Short peptides lie flat in the groove
what are anchor residues?
can be hydrogen bonds between the protein binding groove and the protein
what is the feature of MHC-I that means it binds smaller peptides?
MHC-I has conversed amino acid residues that bind the two ends of a peptide, meaning that it cannot be too long
why can MHC-II bind bigger peptides that MHC-I?
MHC-II lacks the conserved amino acid residues that MHC-I has, and so the peptide lies in an extending conformation within the peptide binding groove
what are polymorphisms?
mutations that have been selected for by evolution and are now distributed throughout the species
how is MHC genetically expressed?
codominantly
where are the majority of MHC polymorphisms found?
in the region that contacts the peptide
what is the role of Non-classical MHC-I?
acts as a stress ligand
- binds to lipids and lipid like molecules
what MHC is important for stimulating natural killer cells?
MICA
MICB - both types of non-classical MHC-I
what is the role of non-classical MHC CD1?
CD1 family allows presentation of glycolipids to NK-T cells
what is the affinity of MHC peptide interactions?
Low affinity
how does a T cell receptor recognize MHC?
T cell receptors recognise the MHC with peptide bound as a complex
how do peptides get presented on MHC-I?
Proteins are degraded into peptides within the cytoplasm and most are destined to be presented on MHC
- the proteins a tagged by ubiquitin for destruction within the cell via the proteisome
Cross-presentation also provides a source of protein to be expressed on MHC-I
what does cross-priming allow?
Exogenous protein to enter the MHC-I pathway
what are DRiPs?
Defective ribosomal products, also called primary translation products
the result of improper RNA splicing, translation of frameshifts, improperly folded proteins, stalling ribosomes
how do DRiPs become expressed on MHC-I?
DRiPs are immediately degrade by the proteasome and so then can be expressed on MHC-I
what is a proteasome?
Protease complex present in the cytoplasm
what is the role of the proteasome?
Proteins are tagged for processing by the addition of the protein ubiquitin
- proteins are then broken down into short peptides
what induces the immunoproteasome?
Interferons and alters processing of peptides
what is the function of the immunoproteasome?
increases protein cleavage after hydrophobic residues and decreased cleavage after acidic residues
- this results in the generation of peptides able to be transported by TAP and with better terminal anchor residues for insertion into MHC-I
what are TAPs?
Transporter associated with Antigen Processing
what is the role of TAPs?
imports peptides into the ER
what are some examples of protein chaperones?
calnexin
Calreticulin
ERp57
tapasin
what is the role of chaperon proteins?
Maintain MHC-I structure in the absence of peptide
what is ERAAP?
Endoplasmic Reticulum Aminopeptidase associated with Antigen Processing
what is the function of ERAAP?
trims peptides to optimal length
what regulates ERAAP?
Upregulated by IFNg
what is MHC-II expression controlled by?
Master transcription factor CIITA
what is the role of master transcription factor CIITA?
ensures specific expression by antigen-presenting cells
what is the role of HLA-DM?
Binds to and stabilises empty MHC-II and catalyses the release of CLIP from MHC-II
