MHC lecture 7

Question 1

what is the Major histocompatability complex

Answer 1

a large genetic locus on chromosome 6 that codes for MHC class 1 and 2 molecules and many other proteins involved in processing and presentation of antigen.

Question 2

MHC1 structure

Answer 2

alpha chain non covalently linked to a small beta2 microglobulin
- groove fomred by alpha1 and 2 domains, supported by alpha 3 and beta 2 micro

Question 3

how many domains does the alpha chain have

Answer 3

3 in mhc1 but 2 in mhc2

Question 4

size of peptide binding groove

Answer 4

8-9 amino acids

- beta pleated sheet with a alphahelix on the 2 sides

Question 5

structure of MHC2

Answer 5

an alpha and a beta chain of basically the same size

- binding groove formed by alpha 1 and beta1 domains, supported by alpha2 and beta2

Question 6

MHC1 and 2 size of peptides acocomodated

Answer 6

1 = 9 amino acids , pockets at ach end to interactwith carboxy terminus. 10 aa if it bends

2 = open ended so 13-25 aa.

Question 7

2 ways that MHC is designed so that it can present any antigen

Answer 7

1 - polygeny

2 - polymorphism

Question 8

describe MHC polygeny

Answer 8

3 loci for 1 (HLA-A,B,C) and for 2 (HLA-DP,DQ,DR). each is a different isotype

Question 9

describe MHC polymorphism

Answer 9

many different forms of the genes within the population. over 250 alleles at some loci. often differ by many aa. the allelic polymorphism is thought to be pathogen driven

Question 10

what are haplotypes

Answer 10

MHC loci are closely linked and so are often inherited together as haplotypes.

• the alleles are codominantly expressed ie both maternal and paternal types on the same cell.
• the polymorphism at each of these loci make it basically impossible to express the same combination of alleles as another individual.

Question 11

where is the MHC variability concentrated

Answer 11

in the peptide binding groove.

- the TCR can only bind a particular MHC-peptide combination in what is called MHC restriction

Question 12

what are anchor residues

Answer 12

aa at certain positions of a bound peptide that must always be the same in order to interact with specific pockets in the binding groove

• they anchor the peptide in the groove and determine the peptide binding motif for that MHC molecule.
• non anchor residues can vary
• the MHCs have to have low specificity or they wont be able to bind any of the peptides made from small genome viruses

Question 13

origin of peptides for MHC 1

Answer 13

endogenous. for CD8 T cells

Question 14

origin of peptides for MHC 2

Answer 14

exogenous

Question 15

endogenous pathway of peptide presentation

Answer 15

proteins in the cytosol continually broken down into peptides, mainly by the proteasome.
- peptides moved into the ER via TAP1 and 2 heterodimer
- suitable peptides are loadedd onto partially folded classs 1 molecules by a series of chaperones that make up the peptide loading complex
the loaded MHC 1 is then released from the chaperones and follows the secretory pathway via the golgi to the surface

Question 16

exogenous pathway of peptide presentation

Answer 16

MHC2 in the ER, to prevent peptide binding, the alpha/beta chains associate with the invariant chain which
1 - blocks the peptide binding groove
2 - acts as a folding chaperone
3 - targets the class 2 into the enodcytic pathways

• the complex passes out the ER through the golgi to the endocytic vesicles. here Ii is partially removed to leave the fragement called CLIP in the peptide binding groove.
• antigens are taken up by the endocytic pathway are degraded by proteases.
• within peptide loading compartments known as M2C compartments, CLIP is removed and the appropriate antigen deriveed peptides are loaded.
• the MHC2 - peptide complex is then transported to the surface