Role of the 37 kDa laminin receptor precursor in the life cycle of prions

Prions are thought to consist of infectious proteins that cause, in the abs ence of detectable nucleic acid, a group of fatal neurodegenerative disease s, called transmissible spongiform encephalopathies (TSE). Among these dise ases are bovine spongiform encephalopathy (BSE), scrapie of sheep and Creut zfeldt-Jakob disease (CJD) in humans. They occur as sporadic, infectious or genetic disorders and have in common the accumulation of an abnormal, path ogenic isoform of the cellular prion protein PrPc which is converted in a p osttranslational process into PrPSc concomitant with conformational changes of the protein. During this process PrPc acquires a high beta-sheet conten t and becomes partially resistant to proteases. The mechanism of this conve rsion as well as the physiological function of the cellular prion protein P rPc are poorly understood, but studies employing PrP knock-out mice demonst rated that PrPc is required for the development of prion diseases. The invo lvement of co-factors such as chaperones, receptors or an unknown protein, designated "protein X" in the conversion process are discussed. In a east t wo-hybrid screen we have identified the 37 kDa laminin receptor precursor ( LRP) as an interactor of the cellular prion protein and this interaction co uld be confirmed by co-infection and co-transfection studies in mammalian a nd insect cells. LRP evolved from the ribosomal protein p40 essential for p rotein synthesis lacking any laminin binding activity to a cell surface rec eptor binding laminin, elastin and carbohydrates. The gene encoding 37 kDa LRP/p40 has been identified in a variety of species including the sea urchi n Urechis caupo, Chlorohydra viridissima, the archaebacterium Haloarcula ma rismortui, the yeast Saccharomyces cerevisiae as well as in mammals where i t is highly conserved. LRP works as a receptor for alphaviruses and is asso ciated with the metastatic potential of solid humors where it was first ide ntified. The 37 kDa LRP forms its mature 67 kDa isoform with high laminin b inding capacity by an unknown mechanism involving acylation. The multifunct ionality of LRP as a ribosomal protein and a cell surface receptor for infe ctious agents such as viruses and prions might be extended by additional pr operties. (C) 1999 Elsevier, Paris.