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Tim,
thanks for YOUR explanations and post
explanations. YOu were not much clearer than Prusiner, who (I read the URLs, not
the entire 56 p Nobel lecture, of course) either did not want to disclose or did
not know the whole story what he invented. Nomenclature adds nicely to the
consfusion.
Prions are identified mostly by what they are
(do) NOT. I don't know why a protein 'should' contain DNA or RNA at all? I
thought I have a vague idea about them, not anymore. What ar
they?
(Prion is what prion does, sometime infetious,
sometimes not, etc.)
And why do you (does he) call a different
folding a misfolding?
Of course conformation can expose or hide
specific hooks for action, so a flat (beta) format is acting quite differently
from a quadruple helix rod-format.
I like Jamie's biol nanotube metaphor.
Fact is: we know precious little about proteins,
they are too big and "complex" for the existing methods of investigation. We
notice superficial characteristics and "dream up" possible mechanisms, based on
the desultory knowledge we have. Imagine the cure for the black death in the
14th c. Praying. I just heard on TV that in Washington state there were extra
praying sessions to avert the mad cow catastrophy.
In the meantime nobody knows how the
self-replicating elements of the 'bad' prions survive transition through other
animals, pigs, chickens, etc. and revitalize when we eat those animal tissues.
They swiftly found out that it all came from
Canada, so the damage will be collectible.
Anyway, thanks for the help and
references.
John M
----- Original Message -----
Sent: Saturday, December 27, 2003 11:16
PM
Subject: Re: Prion research and mad cow
disease
Well, I think I
have to amend my remarks. After reading a bit more of Prusiner's work I
think I seriously mis-stated when I said that "prion" does not only refer
to "misfolded" version of certain proteins. I was getting confused in his
usage of the two terms 'prion' and 'prion protein'. :(
'Prion' is more
like a term referring mostly to function: to what a certain 'some thing'
does. 'PrPSc' refers to the specific physical entity which comprises
the 'some thing'.
So, it appears
that Prusiner uses the term 'prion' to refer only to
the pathological entity that is composed of
the "misfolded" version of a PrP.
(from: "Prions
in Skeletal Muscles", 2002)
Prions
cause neurodegenerative diseases, including Creutzfeldt-Jakob disease (CJD),
bovine spongiform encephalopathy (BSE), chronic wasting disease
(CWD), and scrapie in mammals (1).
The only known constituent of the infectious prion is an aberrant
isoform (PrPSc) of the normal cellular (PrPC)
prion protein (PrP). PrPC is a cell-surface glycoprotein, the
_expression_ of which is necessary for the production of prions (2, 3). In animals
with clinical signs of scrapie, the highest levels of prions are
found in the brain and spinal cord, but other tissues,
particularly those of the reticuloendothelial system, exhibit
substantial prion titers
Also,
from his UCSF website:
Nascent prions
are created either spontaneously by mutation of a host protein or by
exposure to an exogenous source. Prions are composed largely, if not
entirely, of a modified form of the prion protein (PrP) designated PrPSc.
Like other infectious pathogens, they multiply but prions do not have a
nucleic acid genome to direct the synthesis of their progeny. A
post-translational, conformational change features in the conversion of
cellular PrP (PrPC) into PrPSc during which alpha-helices are transformed
into beta-sheets. Since this structural transition in PrP underlies both the
replication of prions and the pathogenesis of CNS degeneration, much of the
effort in the laboratory is devoted to elucidating the molecular events
responsible for this process. Indeed, prion diseases seem to be disorders of
protein conformation.
So, this changes
several of my remarks as follows:
This is just
plain wrong:
So,
when talking about a prion-caused disease, we should
probably not say that "the prion causes x", but rather something
like: "PrPSc causes x" or "the pathological isoform of PrP causes x".
Otherwise, we would be saying something analogous to "genes cause x" when we
really mean that "mutated genes cause x".
This is also largely
wrong:
When
is a protein a prion?
The
answer to this is still a bit unclear to me. I speculate from what I read
that a protein can be a called a prion based not necessarily on
specific amino acid sequence (which varies with species), but on some
(mostly) functional criteria:
1) if a
protein is coded for in the genome of the species under
study
2) and
if it can be folded into the two isoforms representing PrPC and
PrPSc
3) and
if the PrPC isoform is normally occurring and functional in the species
under study
4) and if the PrPSc isoform is not
functional in that species
5) and
if the PrPSc isoform can convert the PrPC in the organism into
PrPSc
6) and
if the PrPSc isoform is highly resistant to destruction by
proteasomes.
Sorry for those
errors. That's what I get for rushing to post rather than waiting and
researching more. :(
Tim
Hi
JohnM,
I was a bit
hazy on what 'prion' exactly referred to myself. Here's what I've dug
up.
Prion - short
for "proteinaceous infectious particle", specifically ones that lacks
nucleic acid (see quote below). The term was coined by Stanley Prusiner at
Univ. of Cal. Med School in 1982. Prions are proteins and contain no
RNA or DNA. he won a Nobel Price for his work on prions in 1997.
PrP - short for "prion protein".
From what I
read, neither "prion" nor "PrP" automatically imply that
they refer only to the "misfolded" version of
the proteins. However, many websites talk about prions
as if the term 'prion' did refer only to the "misfolded" versions. Those
sites appear to me to be incorrect.
Prusiner's
Nobel lecture (in PDF form):
Prusiner's paper in "Science" (1997, No. 5336,
Oct., p. 245-251) is available free at:
In the Science
paper, footnote 1 is as follows:
Prions are defined as proteinaceous
infectious particles that lack nucleic acid. PrPC is the
cellular prion protein; PrPSc is the pathologic isoform.
Amino-terminal truncation during limited proteolysis of PrPSc
produces PrP 27-30 (so named because this protease-resistant core of
PrPSc migrates at ~27 to 30 kD).
Further on in
the paper:
PrPSc is the major, and
very probably the only, component of the infectious prion particle.
PrPSc formation is a posttranslational process involving only a
conformational change in PrPC
So,
when talking about a prion-caused disease, we should
probably not say that "the prion causes x", but rather something
like: "PrPSc causes x" or "the pathological isoform of PrP causes x".
Otherwise, we would be saying something analogous to "genes cause x" when we
really mean that "mutated genes cause x".
I am uncertain
if all currently identified pathological isoforms of prions are
termed "PrPSc", or if there are other terms (for pathological isoforms of
PrP found in some other species, for example), but I believe it does refer
to all forms, even though the "Sc" in "PrPSc" apparently initially was a
reference to scrapie (the sheep version of BSE). From the Nobel
lecture:
"The amino acid sequence of PrPSc
corresponds to that encoded by the PrP gene of the mammalian host in which
it last replicated. In constrast to pathogens with a nucleinc-acid genome
that encodes strain-specific properties in genes, prions encipher these
properties in the tertiary structure of PrPSc." (p.
4)
When is a
protein a prion?
The answer to
this is still a bit unclear to me. I speculate from what I read that a
protein can be a called a prion based not necessarily on specific amino acid
sequence (which varies with species), but on some (mostly) functional
criteria:
1) if a
protein is coded for in the genome of the species under
study
2) and if it
can be folded into the two isoforms representing PrPC and
PrPSc
3) and if the
PrPC isoform is normally occurring and functional in the species under
study
4) and if the PrPSc isoform is not functional in
that species
5) and if the
PrPSc isoform can convert the PrPC in the organism into
PrPSc
6) and if the
PrPSc isoform is highly resistant to destruction by
proteasomes.
Other "what is
a prion?" sites:
Regards,
Tim
Tim and All,
I told several times that I am a
virgin-minded layman (=stupid) in the biology-related sciences up from the
macromolecules. Question:
in superficial reading I got the
impression that "PRION" is used as the specific villain in mad cow
disease. I thought it is a 'small' piece of proteinatious molecule with an
inorderly folding. Maybe the latter is pertinent to MCD only and prions
can be 'orderly folded protein
midgets' with RNA only, as well? Many
other animals (fish, etc.) have prions, do they spread mad fish disease? I
don't think so.
I find it unreasonable to 'wait 30 months'
or any, since infected remnants (mentioned are: placentas) of MCD
cows stay for years in pastures ready to infect deer, hare etc, which
then do the favor for the coyotes, wolves, people and other predators.
That is pertinent to PA, NJ, NY, MN, and all other states as well, not
only the West.
Agribiz - as any other successful biz does
not care beyond making money today. That's why that stupid law was
concocted in the US.
Suicidal behavior? for the others. Not for
"me". The government owning oligarchy will feed safely on their private
(organic) sources of their food staple, even if millions fall over like
mad cows.
Protein folding is big deal. I made
experiments myself (El Micr.-ly controlled) "straightening out" protein
(and the like) molecules, froze them in unfolded state, then restored the
mobility and it reformed the orig. folding perfectly, no matter in what
'changed' environment. So a "misfolding" is more than an esthetic
nuisance.
It forms the joining sites (or hides them)
for enzymes, etc., so the conformation is a fundamental adage to the "life
processes".
I asked the question in the 1st par
because it seems that we have mixed info and I don't have the time to
study along books on the proteinatious materials of recent. The old ones I
know do not include the word prion. Just as the recent ones do not include
words which will be coined in the future, when we (hopefully) will learn
more about nature. We can use more knowledge.
I hope the US science will come up with a
better SAFE solution than cremating 45million cows (and bulls!). It's a
mad mad world.
John M
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