Re: How does the structural transformation occur in prion protein?

Hi Robert!

Here is a possible answer to your query

Basics-
Prion is a term 1st used to describe the mysterious infectious agent 
responsible for several neurodegenerative diseases found in mammals like 
Creutzfeldt-Jacob Disease(CJD), Scrapie(an animal transmissible spongiform 
encephalopathy), Kuru(degenerative brain disease of cannibles) and 
Gerstmann-Straussler-Scheinker syndrome(animal variant of CJD).  Prions 
are naturally produced in the brains of all mammals.
The term prion was 1st coined by Stanley B. Prusiner of University of 
California School of medicine at San Francisco in 1982 to distinguish the 
infectious agent that causes scrapie in sheep, CJD in humans and bovine 
spongiform in cattle from other typical infectious agents.
Mutation or change in the sequence of the amino acids in the normal prion 
causes the disorders.  This disease causing prion protein is known as 
ROGUE PRION PROTEIN.

Main part-
In initial stages of prion research it was believed that the infection 
agent consists primarily of a protein found in the membranes of normal 
cells with altered shape or conformation.  The protein changes itself into 
an abnormal form.

Mechanism-
Normal cellular protein, called PrP (proteinaceous infectious particle) is 
centrally involved in the spread of prion diseases.  The protein consists 
about 250 amino acids.  Cellular protein PrP is the sole causative agent 
of prion diseases.  In normal conditions, PrP is in a stable shape (Sn).  
This form never leads to any disorders.  The protein can be flipped into 
an abnormal shape (Sa), and here lies the problem.  Once the protein 
becomes abnormal, it has tendency to convert normal proteins to abnormal 
ones. When a mutation occurs, the normal proteins get easily destabilized 
to abnormal ones.  Still lot of work has to be carried out to know why the 
Sa structure of protein results in neurodegradation.
There is also change in the amino acid sequence of normal prion to 
infectious prion.

Conclusion-
The main reason for the disorders is the ability of the ROGUE PRION 
PROTEIN or the MUTANT form of the normal prion to convert the normal form 
to infectious one.

References-
Journals
1.Novel Proteinaceous Infectious Particles Cause Scrapie - Stanley B. 
Prusiner, Science, 216, 136 - 144 (1982) 
2.The Prion diseases - Stanley B. Prusiner, Scientific American, Jan 1995.
3.Binding of disease-associated prion protein plasminogen - Michael B. 
Fisher et al, Nature, 408, 6811, 479-483, Nov 23, 2000

Websites-
Illustration of prion replication and spread at cellular level - 
www.rkm.com.au/BSE
Details about Mad Cow disease/ BSE - www.mad-cow.org
Link to prions - www.mad-cow.org/~tom/prion_evol.html


Shashank HARITHSA
April 11, 2001