The Prion Paradox: Infection or PolymerizationNULLJan C. Biro1
1Jan.email@example.com, Homulus Informatics
There is a weak but significant similarity between the prion protein (PrP) and some transcription factors and Zn-finger proteins. This similarity was discovered by a new sequence similarity searching method, the blastNP. (blastP applied on overlappingly translated nucleic acids). A possible interpretation of this similarity is that the PrP is a metal- (copper-) binding transcription factor and might behave like a Zn-finger protein: 1., The Cu++ binds to the histidine and serine residues of the PrPC., 2., the Cu++ -binding creates intra-molecular bridges in the PrPC molecule, but 3., inter-molecular bridges in the PrPSc molecule.
A molecular model of the Cu++-binding monomeric (normal, cytoplasmic) PrPC and the Cu++-stabilized polymeric (scrapie - pathogenic) PrPSc is presented and is called the CUPRION model. The PrPC has two idioforms in the “cuprion model”. The stable, normal PrPC idioform-I contains Cu2+ in -2His-Cu2+-2His- complex and an intra-molecular disulphide bridge. An instable, transient PrPC idioform-II contains -2His-Cu2+-2Cys- complex and destabilizes the intra-molecular disulphide bridge making the PrPC molecule highly reactive with other PrPC molecules. The PrPC idioform-II might be the result of mutation, inherited or acquired. The outcome of PrPC idioform-II formation is the massive polymerization of the PrPC into PrPSc and amyloid formation, which is un-degradable and causes cell death.
Key words: prion, molecular modeling, transcriptions factor, Zn-finger, metallo-protein,