The prion paradox: infection or polymerisation?
A weak but significant similarity was found between the prion protein (PrP) and some transcription factors and zinc-finger proteins. 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, with the Cu2+ binding to its histidine and serine residues. Copper-binding could create intramolecular bridges in the PrPC (normal, cytoplasmic) molecule, but intermolecular bridges in the PrPSc (scrapie pathogenic) molecule. A molecular model of the Cu2+ -binding monomeric PrPC and the Cu2+-stabilised polymeric PrP Sc is presented here and named the 'cuprion model'. In this model, the PrPC has two idioforms. The stable, normal PrPC-idioform-I contains Cu2+ in -2His-Cu2+-2His- complexes and an intramolecular disulphide bridge. An unstable, transient form, PrPC-idioform-II, contains a -2His-Cu 2+-2Cys- complex, which destabilises the intramolecular disulphide bridge and makes the PrPC molecule highly reactive with other PrPC molecules.
Biro
Jan C
JC
Homulus Informatics, San Francisco, CA 94105, USA. jan.brio@kbh.ki.se
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002494:Central Nervous System Infections / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D014157:Transcription Factors