Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease.

Highly abundant in neurons, the cellular prion protein (PrP) is an obligatory precursor to the disease-associated misfolded isoform denoted PrP that accumulates in the rare neurodegenerative disorders referred to either as transmissible spongiform encephalopathies (TSEs) or as prion diseases. The ability of PrP to serve as a substrate for this template-mediated conversion process depends on several criteria but importantly includes the presence or absence of certain endoproteolytic events performed at the cell surface or in acidic endolysosomal compartments. The major endoproteolytic events affecting PrP are referred to as α- and β-cleavages, and in this review we outline the sites within PrP at which the cleavages occur, the mechanisms potentially responsible and their relevance to pathology.

Wombat burrows are hotspots for small vertebrates in a landscape subject to gigafire.

Ecosystem engineers modify their environment and influence the availability of resources for other organisms. Burrowing species, a subset of allogenic engineers, are gaining recognition as ecological facilitators. Burrows created by these species provide habitat for a diverse array of other organisms.

Application of N-Terminal Labeling Methods Provide Novel Insights into Endoproteolysis of the Prion Protein .

Alternative α- and β-cleavage events in the cellular prion protein (PrP) central region generate fragments with distinct biochemical features that affect prion disease pathogenesis, but the assignment of precise cleavage positions has proven challenging. Exploiting mouse transgenic models expressing wild-type (WT) PrP and an octarepeat region mutant allele (S3) with increased β-fragmentation, cleavage sites were defined using LC-MS/MS in conjunction with N-terminal enzymatic labeling and chemical in-gel acetylation. Our studies profile the net proteolytic repertoire of the adult brain, as deduced from defining hundreds of proteolytic events in other proteins, and position individual cleavage events in PrP α- and β-target areas imputed from earlier, lower resolution methods; these latter analyses established site heterogeneity, with six cleavage sites positioned in the β-cleavage region of WT PrP and nine positions for S3 PrP.

Beta-endoproteolysis of the cellular prion protein by dipeptidyl peptidase-4 and fibroblast activation protein.

The cellular prion protein (PrP) converts to alternatively folded pathogenic conformations (PrP) in prion infections and binds neurotoxic oligomers formed by amyloid-β α-synuclein, and tau. β-Endoproteolysis, which splits PrP into N- and C-terminal fragments (N2 and C2, respectively), is of interest because a protease-resistant, C2-sized fragment (C2) accumulates in the brain during prion infections, seemingly comprising the majority of PrP at disease endpoint in mice. However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in vivo.