Prion protein structural features indicate possible relations to signal peptidases

Transmissible spongiform encephalopathies (TSEs) in mammalian species are believed to be caused by an oligomeric isoform, PrP Sc , of the cellular prion protein, PrP C . One of the key questions in TSE research is how the observed accumulation of PrP Sc , or possibly the concomitant depletion of PrP C can cause fatal brain damage. Elucidation of the so far unknown function of PrP C is therefore of crucial importance. PrP C is a membrane-anchored cell surface protein that possesses a so far unique three-dimensional structure. While the N-terminal segment 23–120 of PrP C is flexibly disordered, its C-terminal residues 121–231 form a globular domain with three α-helices and a two-stranded β-sheet. Here we report the observation of structural similarities between the domain of PrP(121–231) and the soluble domains of membrane-anchored signal peptidases. At the level of the primary structure we find 23% identity and 41% similarity between residues 121–217 of the C-terminal domain of murine PrP and a catalytic domain of the rat signal peptidase. The invariant PrP residues Tyr-128 and His-177 align with the two presumed active-site residues of signal peptidases and are in close spatial proximity in the three-dimensional structure of PrP(121–231).