β-Cleavage of the prion protein in the human eye: Implications for the spread of infectious prions and human ocular disorders

Chaudhary, Suman; Ashok, Ajay; Wise, Aaron; Rana, Neil; Kritikos, Alexander E; Lindner, Ewald; Singh, Neena

doi:10.1016/j.exer.2021.108787

Cited by 2 publications

(2 citation statements)

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“…The α-cleavage is considered one of the most abundant fragmentation events targeting PrP C ; C1 fragment generated by this proteolytic event contributes to approximately 50% of total PrP C in the CNS. 12 The cleavage event targets a region at the beginning of the hydrophobic domain (HD) (within residues 109−112), with a relevant cleavage observed between H110↓V111, 13 generating a soluble N-terminal fragment of approximately 11 kDa (N1) and a membrane-bound C-terminal fragment (C1) of ∼16 kDa. Members of the "a disintegrin and metalloprotease" (ADAM) family of proteases are believed to be responsible for this cleavage event.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Neither the precise location of the cleavage site nor the precise proteases responsible for most of these are conclusive. The α-cleavage is considered one of the most abundant fragmentation events targeting PrP C ; C1 fragment generated by this proteolytic event contributes to approximately 50% of total PrP C in the CNS . The cleavage event targets a region at the beginning of the hydrophobic domain (HD) (within residues 109–112), with a relevant cleavage observed between H110↓V111, generating a soluble N-terminal fragment of approximately 11 kDa (N1) and a membrane-bound C-terminal fragment (C1) of ∼16 kDa.…”

Section: Introductionmentioning

confidence: 99%

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

Gomez-Cardona,

Eskandari-Sedighi,

Fahlman

et al. 2023

ACS Chem. Neurosci.

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Alternative αand β-cleavage events in the cellular prion protein (PrP C ) 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 wildtype (WT) PrP C 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 C αand 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 C and nine positions for S3 PrP C . Regarding α-cleavage, aside from reported N-termini at His110 and Val111, we identified a total of five shorter fragments in the brain of both mice lines. We infer that aminopeptidase activity in the brain could contribute to the ragged N-termini observed around PrP C 's αand β-cleavage sites, with this work providing a point of departure for further in vivo studies of brain proteases.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%