The 'protein-only' hypothesis for the infectivity of prions in diseases such as bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD) contends that the cellular protein PrPC is converted into a pathologically misfolded state, called PrPSC. PrPSC, like many misfolded proteins involved in disease, forms insoluble aggregates that have a predominantly β-sheet structure, which is vastly different to the α-helix-rich structure of PrPC. This leads to the obvious question: could there be any conformational differences between these two isoforms that might allow PrPSC to be specifically targeted by drugs?

Cashman and colleagues proposed that the conversion to the poorly soluble PrPSC isoform could allow hydrophobic amino acids that are normally hidden within PrPC to become exposed on the protein surface. Clusters of these amino acids could form unique immunological epitopes for the selective antibody recognition of PrPSC.

Reporting in Nature Medicine, the authors found that induction of β-sheet structures in recombinant cellular prion proteins (by lowering pH) is associated with the increased accessibility of tyrosine residues. Sequence alignments of the cellular proteins in several organisms showed that most tyrosine residues are found in pairs — two of which have a tyrosine-tyrosine-arginine (Tyr-Tyr-Arg) sequence. Immunoprecipitation, plate capture immunoassay and flow cytometry showed that antibodies directed against this Tyr-Tyr-Arg motif recognize the pathological isoform of the prion protein but not the normal cellular isoform. Antibody competition experiments showed that binding to the pathological Tyr-Tyr-Arg epitope is saturable and specific. In addition, the epitope could be created in vitro by partial denaturation of normal brain prion protein.

The Tyr-Tyr-Arg motif is the first conformation-selective epitope to be identified. Cashman and colleagues suggest that the exposure of previously sequestered amino-acid side chains that accompanies the conformational conversion of the prion protein could provide a prototype for other disorders of protein misfolding, including Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. Exploitation of this 'side-chain accessibility' hypothesis, say the authors, might provide new diagnostic and therapeutic approaches to several post-translational disorders of the proteome.