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, PrPSc, of the cell ular prion protein, PrPC. One of the key questions in TSE research is how the observed accumulation of PrPSc, or possibly the concomitant de pletion of PrPC can cause fatal brain damage. Elucidation of the so fa r unknown function of PrPC is therefore of crucial importance. PrPC is a membrane-anchored cell surface protein that possesses a so far uniq ue three-dimensional structure. While the N-terminal segment 23-120 of PrPC is flexibly disordered, its C-terminal residues 121-231 form a g lobular domain with three alpha-helices and a two-stranded beta-sheet. Here we report the observation of structural similarities between the domain of PrP(121-231) and the soluble domains of membrane-anchored s ignal peptidases. At the level of the primary structure we find 23% id entity and 41% similarity between residues 121-217 of the C-terminal d omain 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 pr esumed active-site residues of signal peptidases and are in close spat ial proximity in the three-dimensional structure of PrP(121-231). (C) 1998 Federation of European Biochemical Societies.