α-Cleavage of cellular prion protein

Figures & data

Figure 1. Schematic diagram of PrP processing. PrP is known to be cleaved at 3 sites: after residue 110 or 111 (α-cleavage), near the end of the octapeptide repeats region (β-cleavage), and at or near the GPI anchor (shedding). The amino acid numbering is based on human PrP. CHO: Asn-linked glycans; -S-S-: disulfide bridge; ROS: reactive oxygen species. The enzymes/factors involved in the processing are highlighted in green, and question marks denote the existence of conflicting reports on the respective protease(s).

Table 1. Proteases and factors implicated in the α-cleavage of PrP^C

Factors involved	References	Results
ADAM8	Liang et al. (2012)	ADAM8 is the primary protease responsible for α-cleavage of PrP^C in muscles.
ADAM10	Vincent et al. (2001)	ADAM10 appears to be a protease candidate responsible for constitutive α-cleavage of PrP^C.
	Taylor et al. (2009)	The bulk of the cell-associated endoproteolytic α-cleavage of PrP^C does not require ADAM10.
	Laffont-Proust et al. (2005)	High levels of C1 are associated with the presence of the active ADAM10 in the human brain.
	Endres et al. (2009)	Neuronal overexpression of ADAM10 diminished the amount of PrP^C instead of increasing its α-cleavage in vivo.
	Altmeppen et al. (2011)	ADAM10 is not responsible for the α-cleavage of PrP^C in neurons using neuron-specific ADAM10 knockout mice.
ADAM17	Vincent et al. (2001)	ADAM17 appears mainly involved in phorbol ester regulated α-cleavage of PrP^C.
	Taylor et al. (2009)	The bulk of the cell-associated endoproteolytic α-cleavage of PrP^C does not require ADAM17.
ADAM9	Cisse et al. (2005)	ADAM9 indirectly participates in N1 production, likely via contributing to the shedding of ADAM10.
	Taylor et al. (2009)	The bulk of cell-associated endoproteolytic α-cleavage of PrP^C does not require ADAM9.
Plasmin/ Plasminogen	Kornblatt et al. (2003)	Plasminogen performs α-cleavage of PrP^C in vitro and plasmin accelerates this process.
	Praus et al. (2003)	Plasmin cuts PrP^C in vitro at the α-cleavage site and the resulting N1 fragment accelerates plasminogen activation.
	Barnewitz et al. (2006)	The C1 production in plasminogen knockout mice is unaltered, indicating other proteases in addition to plasmin are responsible for PrP^C α-cleavage in vivo.
Protein kinase C	Vincent et al.(2000)	α-cleavage of PrP^C is upregulated by protein kinase C but not protein kinase A in human cells and murine neurons.
	Cisse et al.(2007)	Activation of protein kinase C-coupled muscarinic receptors M1 and M3 increases the α-cleavage of PrP^C by ADAM17.

Table 2. Proteases and factors implicated in β-cleavage or shedding of PrP

Type of processing	Factors involved	References	Results
β-cleavage	Reactive oxygen species	McMahon et al. (2001)	β-cleavage of PrP^C by reactive oxygen species is copper- and pH-dependent.
		Watt et al. (2005)	ROS-mediated β-cleavage of PrP^C is an early and critical event associated with protection against oxidative stress
	Calpain	Yadavalli et al. (2004)	Calpain mediates β-cleavage of PrP^Sc in prion-infected cells.
	Cathepsin	Dron et al. (2010)	Cathepsin but not calpain inhibitors inhibited C2 formation, indicating that acidic hydrolases of the endolysosomal compartment is involved in the β-cleavage of PrP^Sc that is cell- and tissue-dependent. The N-termini of in vivo and in vitro generated C2 differ.
Shedding near the GPI anchor	ADAM10	Taylor et al. (2009)	ADAM10, but not ADAM17, are involved in the ectodomain shedding of PrP^C. ADAM10 directly cleaves murine PrP between Gly^228 and Arg^229.
		Altmeppen et al. (2011)	ADAM10 is the sheddase of PrP^C in vivo and the lack of ADAM10 leads to increased amounts and accumulation of PrP^C in the early secretory pathway by affecting its posttranslational processing.
	ADAM9	Taylor et al. (2009)	ADAM9 is involved in the ectodomain shedding of PrP^C via ADAM10.
Shedding at the GPI anchor	Phospholipase	Parkin et al. (2004)	Lipid raft-disrupting agent-mediated shedding of PrP^C is likely to occur via phospholipase cleavage of the GPI anchor