Prion protein structural features indicate possible relations to signal peptidases

AbstractTransmissible spongiform encephalopathies (TSEs) in mammalian species are believed to be caused by an oligomeric isoform, PrPSc, of the cellular prion protein, PrPC. One of the key questions in TSE research is how the observed accumulation of PrPSc, or possibly the concomitant depletion of PrPC can cause fatal brain damage. Elucidation of the so far unknown function of PrPC is therefore of crucial importance. PrPC is a membrane-anchored cell surface protein that possesses a so far unique three-dimensional structure. While the N-terminal segment 23–120 of PrPC 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)