Bovine encephalopathy

Mr Neville Steven Percy spbcnsp at ucl.ac.uk
Tue Apr 26 15:16:22 EST 1994

R.Burge at bay.cc.kcl.ac.uk (Richard Burge) writes:
>In article <2p8vaq$jd3 at mule.fhcrc.org> Tim Buss <tbuss at fred.fhcrc.org> writes:

>>What does the wild-type prion protein actually do??

>Good question - it is is highly conserved between species (c. 95% or so 
>between mammalian species), suggesting it has some important physiological 
>role. However, knockout mice that are prp negative appear completely normal 
>and have normal lifespans, plus they are resistant to prion disease (they 
>don't develop prion diseases from intracerebroventricular injection of active 
>prions). Heterozygotes (prp +/-) are still subsceptible to prion disease, but 
>there is a longer latency between intracerebroventricular injection of prions 
>and actual onset of any symptoms, compared to wild-type.

>Maybe we could make a transgenic cow - it'd revolutionise British farming!

Well what we do know is that it's a smallish (MW 33-35 kDa) protein with two
sites at whic variable glycosylations occur.  These are responsible for the
variability in MW, and no one has been able to suss any system to them as yet, 
except that sialic acid residues predominate.  Sialic acid is the only sugar
which has a nett negative charge, and from what I can gather, it is fairly rare.
The only thing is, literature-searching along the lines of what do (...
sialoglycoproteins do? still comes up with a shit load of stuff, with no
discernable pattern.
Does anyone out there know what is significant about sialic acid?

The protein has one S=S, and a cleaved-off signal peptide for crossing the 
membrane, where it is held on the outside of the cell by a GPI (...
(glycophosphoinositol) anchor.  Studies have suggested quite varied times for
its half-life at the membrane, but all agreed this was short.

Combining its low abundance, variable glycosylation, and rapid turnover, most
people are currently happy to assume it has some sort of signalling function
between adjacent cells.  The quest to discover its actual function has fallen on
the wayside compared to its pathological qualities, despite the insights we 
could get from knowing its normal function.

I should also say that just because the knockout PrP-null mice don't appear to
suffer any ill effects from this lack, doesn't mean that PrP isn't doing 
something really crucial.  There is a strong precedent from bacterial work that
when a protein is _utterly_ crucial, it has a back-up; this could be masking
more-or-less any consequences of knocking out the PrP.

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                                                   Nev Percy ; spbcnsp at ucl.ac.uk                

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