Alpha‐ and beta‐ cleavages of the amino‐terminus of the cellular prion protein

Abstract

It is commonly assumed that the physiological isoform of prion protein, PrP C , is cleaved during its normal processing between residues 111/112, whereas the pathogenic isoform, PrP Sc , is cleaved at an alternate site in the octapeptide repeat region around position 90. Here we demonstrated both in cultured cells and in vivo, that PrP C is subject to a complex set of post-translational processing with the molecule being cleaved upstream of position 111/112, in the octapeptide repeat region or at position 96. PrP has therefore two main cleavage sites that we decided to name a and b. Cleavage of PrP C at these sites leads us to re-evaluate the function of both N-and C-terminus fragments thus generated.

Dominant roles of the polybasic proline motif and copper in the PrP23-89-mediated stress protection response

“…In the current study synthetic N-terminal fragments were added exogenously to the extracellular surface to investigate stress protection mediated from outside the cell. Given that PrP C is an extracellular cell-surface protein and that both N-terminal (N1 and N2) cleavage fragments have been found in higher concentrations in conditioned medium than within cell lysates (Mangé et al, 2004;Vincent et al, 2001), with the N2 fragment increased especially after treatment with hydrogen peroxide and copper (McMahon et al, 2001), it is reasonable to assume that at least part of the Nterminal function is mediated from the outer leaflet of the cell membrane. Rapid degradation following internalisation of these fragments may explain their higher prevalence in the extracellular environment.…”

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

“…Adding complexity, a recent study suggests a-cleavage may actually be multifaceted, with multiple neighboring cleavage sites targeted by different proteases [31]. b-Cleavage, predominantly associated with prion disease and misfolded prion protein conformers (PrP Sc ) [30,32], but also reported to befall PrP C in uninfected cells and tissues [30,[33][34][35][36], involves 'ragged' cleavage at the end of the metal-binding octapeptide repeat region, around residue 90, producing the C2 and N2 fragments [34,35]. The precise biological reasons for PrP C proteolysis are not entirely elucidated, although PrP C proteolytic fragments, especially the C-terminal fragments, are abundant in cells and tissues, and there is increasing evidence for separate roles for the different PrP molecular species [29].…”

PrPCHomodimerization Stimulates the Production of PrPCCleaved Fragments PrPN1 and PrPC1

“…In contrast, its physiological function is still under debate (Roucou et al, 2004;Steele et al, 2007). PrP C undergoes several physiological cleavages, the ␤-and ␣-cleavage, at amino acids 89/90 and 110 -111/112 of human PrP C , respectively; and a cleavage at amino acids 228/229 resulting in ectodomain shedding (Chen et al, 1995;Mangé et al, 2004;Taylor et al, 2009). …”

“…The ␣-cleavage (also termed C1 cleavage) produces a 17 kDa, N-terminally truncated fragment termed PrPC1, anchored to the plasma membrane and a secreted 11 kDa fragment termed PrPN1 (Chen et al, 1995;Mangé et al, 2004). Opposite functions were attributed to PrPC1 (Sunyach et al, 2007;Lewis et al, 2009;Westergard et al, 2011).…”