In article <367gsa$1sk at matt.ksu.ksu.edu>,
Dave Rintoul <drintoul at ksu.ksu.edu> wrote:
>Here we go! As previously noted, I am working on a companion volume
>for a new edition of a major cellbiology text, and am in charge of
>generating questions about such diverse topics as immunology,
>cytoskeletons, ECM etc. The first chapter is immunology; this will be
>crossposted to cellbiology and immunology. Any and all responses will
>be greatly appreciated; all respondents will get credit in the preface
>of the companion volume. Have a go at these, and thanks in advance
[...]
>3. Why do we have an MHC? Why aren't these genes (encoding for
>structurally unrelated proteins such as the class I and class II
>proteins, peptidases, glycosyltransferases, cytokines, peptide
>transporters, and even some mystery genes) scattered about the genome?
I'll have a crack at this one. You wanted just commentary,
right? A Medline search will help you put this on more solid ground
if that's what you need.
The peptide transporters, peptidases, and MHC proteins all work
together in a concerted system. Here's the model (I'm not saying all
this is proven): peptides are cleaved by intracellular peptidases (LMP2,
LMP7) that have some sequence specificity. The peptide transporters
(TAP1, TAP2) may also have some sequence specificity, so that they don't
export just any peptide in the cytoplasm. Lastly, MHC class I molecules
all have some sequence bias as well - a given allele can't possibly bind
all peptides of 8-10 amino acids. BTW, polymorphisms have been demon-
strated in all of these genes.
The reason that all these genes cluster together in a locus is
precisely due to the sequence bias of the components. If you have e.g.
an HLA-B27 gene, and your TAP genes refuse to transport peptides with
arginine at position 2, you're in trouble. I think that sets of genes
that *must* work well together will segregate on the same chromosome
in order to avoid being split up by independent chromosomal segregation
at meiosis. Furthermore, locating the genes close together on the
same chromosome ensures that separation of two coordinating genes by
meiotic recombination is kept to a minimum. Recombination sites within
the MHC may also be under some sort of restriction. In fact, evidence of
"linkage disequilibrium" has been noted in the MHC locus. Population
statistics suggest that certain MHC genes segregate non-randomly.
I've left something out of this picture: why is MHC class II
present in the locus? Since it doesn't need to coordinate (as far as we
know) with the TAP and LMP genes, why is it there? The answer, I think,
is the same as the reason that one finds HLA-A, B, and C together. There
is not only a need for concerted action within the MHC locus, there is also
a need to maintain diversity in peptide presentation. I would guess that
a linkage analysis of HLA genes would find them in disequilibrium, and
that the peptide specificities of HLA molecules within a given class would
be quite divergent for a single individual.
--
Unique ID : Ladasky, John Joseph Jr.
Title : BA Biochemistry, U.C. Berkeley, 1989
Location : Stanford University Dept. of Cell Biology, Fairchild D-105
Keywords : immunology, music, running, Green
