MHC molecules Flashcards
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
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
what is meant by the fact that MHC is polygenic
it is encoded y multiple genes
on which chromosome are MHC genes located
6, except for invariant chain and B2 microglobulin
why is MHC the most polymorphic (hundreds of alleles) region of the genome
to ensure variety antigenic peptides are able to be presented
How are MHCI and II expressed
co-dominantly- express 2 copies of each gene which pair up to form 4 possible proteins
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
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
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
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
which enzyme further trims peptide is the ER to allow binding to MHC I
ER associated amino-peptidase 1
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
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
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
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
