Interactions of prion protein with intracellular proteins: so many partners and no consequences?

Abstract

Prion protein (PrP) plays a key role in the pathogenesis of transmissible spongiform encephalopathies (TSEs)--fatal diseases of the central nervous system. Its physiological function as well as exact role in neurodegeneration remain unclear, hence screens for proteins interacting with PrP seem to be the most promising approach to elucidating these issues. PrP is mostly a plasma membrane-anchored extracellular glycoprotein and only a small fraction resides inside the cell, yet the number of identified intracellular partners of PrP is comparable to that of its membranal or extracellular interactors. Since some TSEs are accompanied by significantly increased levels of cytoplasmic PrP and this fraction of the protein has been found to be neurotoxic, it is of particular interest to characterize the intracellular interactome of PrP. It seems reasonable that at elevated cytoplasmic levels, PrP may exert cytotoxic effect by affecting the physiological functions of its intracellular interactors. This review is focused on the cytoplasmic partners of PrP along with possible consequences of their binding.

Fig. 1

Scheme of human PrP. Signal peptides governing entry into ER lumen (SP ER) and attachment of GPI (SP GPI), octarepeats (OR), transmembrane domain (TM), two nuclear localization signals (NLS), disulfide bridge (S–S), GPI attachment site, two glycosylated asparagine residues (N-Glyc), three α-helices and two β-strands are indicated. Sites of proteolytic processing related to the maturation of PrP and generation of two shortened forms C1 and C2 are marked with scissors