Prion protein induced conversions

Hosszu LLP, Tattum MH, tones S et al (2010) The H187R mutation of the human prion protein induces conversion of recombinant prion protein to the PrP(Sc)-like form. Biochemistry 49 8729-8738... 

Alonso DOV, DeArmond SJ, Cohen FE, Daggett V (2001) Mapping the early steps in the pH-induced conformational conversion of the prion protein. Proc Natl Acad Sci USA 98 2985... 

Protein aggregation is a hallmark of scrapie, and scrapie protein can be induced to aggregate in vitro into forms that are indistinguishable from pathological brain-derived fibrils. Prusiner proposed that prion disease involves a mechanism for autocatalytic conversion of a host... 

Like any other protein, the molecular structure of the prion is subject to conformational flexibility and to various thermal-induced fluctuations between varying conformational states. However, if these fluctuations permit the PrP conformation to be attained, then this abnormal conformer promotes the widespread conversion of PrP to PrP , leading to the precipitous deposition of the abnormal protein throughout the brain (mirrored by the rapid and relentlessly downhill clinical course). This pathological self-propagating shape conversion of a-helical PrP to P-sheet PrP may in principle be initiated by a seed PrP molecule in the neurotoxic conformation. This explains the transmissibility of prion diseases and accounts for how susceptible humans exposed to beef from an animal with mad cow disease develop variant Creutzfeldt-Jakob disease. 

In 2001 Soto and colleagues described a new type of cell-free prion conversion reaction called protein-misfolding cyclic amplification (PMCA) which has greatly improved efficiency, continuity, and sensitivity compared to the initial CFC reactions [11]. In the typical PMCA reaction, crude brain extracts are used as a source of the PrPc which is induced to convert by prions or PrPres in the test sample. Under these conditions, PrPres can be amplified to levels that are detectable... 

Which mechanism could induce such a dramatic change of the 3D structure of a protein How could the a —> p conversion of PrP into PrP " account for the pathogenic properties of this protein In 1967 (25 years before Prusiner invented the term prion), a remarkably inspired mathematician, J. S. Griffith, proposed a simple but prophetic model of a disease caused by the replication of an infectious protein. One of his hypothesis was that the brain expressed a "normal" form of the protein, whereas the infectious particle contained an "abnormal" form of the same protein. The abnormal form of the protein was then supposed to bind to the normal brain protein and to convert it into a disease-causing protein. This simple mechanism... 

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