Ian A. York iayork at
Fri Apr 18 10:19:31 EST 1997

In article <01IHUISINTC28ZYIDX at>,
camlmcz <camlmcz at UBVMS.CC.BUFFALO.EDU> wrote:
>How is that antigenic proteins are able to avoid complete proteotytic 
>cleavage into amino acids during antigen processing?      -- Amy Forand

For MHC class I, the answer isn't proven, but the probable answer is that
the majority of proteins that are channeled into protein degradation
pathways *do* get cleaved down to amino acids; or at any rate are cleaved
to sizes that are inappropriate for MHC binding.  A small proportion (who
knows? --perhaps 1%, though there is undoubtedly a huge variation
depending on the particular protein and on the epitope) escape complete
cleavage and are fed into the MHC I antigen presentation pathway.

If, as seems likely, the majority of antigenic peptides derive from
proteasomal degradation, the problem *may* not be as severe as it seems at
first glance.  Based on the crystal structure of the archaebacterial
proteasome, the active sites of the proteasome are about the right
distance apart to cleave proteins into 8- or 9-mers, the appropriate size
for MHC I.  There are probably (possibly) regulatory components that alter
proteasome processing so that there is a preference for peptides of the
appropriate size.  Although it's difficult to make broad conclusions, the
proteasome in vitro has been shown to like to generate peptides of the
right size. 

For the generic protein degradation pathway, it's possible that the
oligopeptides produced by the proteasome feed into some other cytosolic
degradation pathways for complete degradation (assuming that the
proteasome does not produce amino acids, and this remains possible, I
think).  Peptides introduced into the cytosol are degraded very rapidly: 
although I don't think it's been shown that this is
proteasome-independent, I bet it is.  It is possible that there is/are
some cytosolic component that acts as a ferry for peptides between
proteasome and TAP; or, perhaps, the proteasome may physically associate
with TAP.  There's no evidence for either (except for the extremely
circumstantial, though interesting, data for HSP's mainly from Srivstava's

The above is for class I.  For class II, although there are subtleties
about the pH and the enzymes available in the antigen/MHC association
compartment(s), there is an extremely interesting papers from Unanue's lab
that strongly suggest that the peptide binds to the MHC II peptide-binding
groove as a longer protein and is then degraded, with the groove acting as
protection for the bound peptide.  This probably does not happen for the
class I, incidentally, because based on crystal structure there is no room
for an enzyme active site to get close enough to the class I groove to
generate the observed N- and C-terminal ends (class II N-terminal and
C-terminal ends are further away from the groove than for class I). 

Hope this helps.


      Ian York   (iayork at  <>
      "-but as he was a York, I am rather inclined to suppose him a
       very respectable Man." -Jane Austen, The History of England

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