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Flashcards in MHC molecules Deck (19):
1

describe the structure of MHC I molecule and binding groove

4 extracellular domains form a groove. the groove is made up of a floor of b sheets and walls of a-helices. o antigenic peptide required for correct folding of mhc molecule and should be a length of 8-10aas

2

describe the structure of MHC II molecule and binding groove

4 extracellular domains form a groove. the groove is made up of a floor of b sheets and walls of a-helices.antigenic peptide required for correct folding of mhc molecule but can be of variable length as the binding groove is open ended

3

what is meant by the fact that MHC is polygenic

it is encoded y multiple genes

4

on which chromosome are MHC genes located

6, except for invariant chain and B2 microglobulin

5

why is MHC the most polymorphic (hundreds of alleles) region of the genome

to ensure variety antigenic peptides are able to be presented

6

How are MHCI and II expressed

co-dominantly- express 2 copies of each gene which pair up to form 4 possible proteins

7

describe the molecular basis for MHC I antigen presentation

antigens are processed by the proteasome to form peptides. peptides are transacted into ER lumen. translocation is mediated by TAP. MHC molecules fold in the ER assisted by calnexin and calreticulum (chaperones). When TAP is in complex with the MHC molecule, tapes and chaperones it is known as the loading complex. at this point the antigenic peptide is loaded onto the MHC I molecule. The MHC I molecule bound to antigen traffics through the secretion pathway to the PM for antigen presentation

8

describe how the proteasome generates peptides

The 26s complex recognises proteins which have been tagged for degradation by ubiquitination. the complex possesses 3 forms of protease activity. It cleaves after basic residues via tryptic activity, chymotryptic activity cleaves after hydrophobic residues and peptidylglutamylpeptidase cleaves after acidic residues

9

how does the immunoproteasome differ from the proteasome

IFNg exchanges constitutive subunits for MECL-1, LMP2 and LMP7, altering proteasome specificity reducing cleavage after acidic amino acids as MHC I molecules do no like acidic residues to be at the C-term

10

describe the process of TAP mediated peptide transport into the ER

TAP is a heterodimer encoded in MHC2 region. ATP hydrolysis energises the translocation of peptides of l9-12aa in length and favours hydrophobic residues at the end

11

which enzyme further trims peptide is the ER to allow binding to MHC I

ER associated amino-peptidase 1

12

What is the role of Tapasin in the import of peptides into the ER for MHC I presentation

it stabilises TAP and binds to the MHC molecule to bring them into close proximity and optimise high affinity binding of the peptide

13

describe the MHC II antigen presentation pathway

MHC2 is synthesised in the ER lumen. the invariant chain (CLIP) obscures peptide binding groove to prevent premature binding. this complex exits the ER through the golgi to an endosomal compartment called the MHC II compartment. The invariant chain is removed by proteases enabling peptides which have been taken up by endocytosis and delivered to the compartment to bind the groove

14

aside from preventing premature antigen binding, what other role does the invariant chain play in the MHC II presentation of peptides

it is a trimer of trimers which contains dileucine motifs which are necessary for trafficking the MHCII molecule to the MHC II compartment

15

describe how the invariant chain is processed and then later removed from MHC2 molecules in the MHC2 compartment

The invariant chain is cleaved by AEP forming a p10 chain which is subsequently cleaved by cathepsin S leaving the CLIP peptide in the binding groove. Once in the MHC2 compartment HLA-DM facilitates the release of CLIP, as well as promoting high affinity binding of antigenic peptides in an analogous manner to tapesin

16

How do B cells internalise antigen

via membrane bound antibody

17

how do macrophages internalise antigen

phagocytosis

18

how do DCs internalise antigen

receptor mediated endocytosis
phagocytosis
macropinocytosis

19

describe how antigens are processed as part of the MHC2 presentation pathway

disulphide bonded proteins are first reduced by GILT then cleaved by a huge variety of proteases including a number of cathepsins and AEP. the peptide is then able to bind MHC2 and can be trimmed further if necessary