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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-33110

Oliveira-Martins, J B; Yusa, S I; Calella, A M; Bridel, C; Baumann, F; Dametto, P; Aguzzi, A (2010). Unexpected tolerance of alpha-cleavage of the prion protein to sequence variations. PLoS ONE, 5(2):e9107.

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Abstract

The cellular form of the prion protein, PrP(C), undergoes extensive proteolysis at the alpha site (109K [see text]H110). Expression of non-cleavable PrP(C) mutants in transgenic mice correlates with neurotoxicity, suggesting that alpha-cleavage is important for PrP(C) physiology. To gain insights into the mechanisms of alpha-cleavage, we generated a library of PrP(C) mutants with mutations in the region neighbouring the alpha-cleavage site. The prevalence of C1, the carboxy adduct of alpha-cleavage, was determined for each mutant. In cell lines of disparate origin, C1 prevalence was unaffected by variations in charge and hydrophobicity of the region neighbouring the alpha-cleavage site, and by substitutions of the residues in the palindrome that flanks this site. Instead, alpha-cleavage was size-dependently impaired by deletions within the domain 106-119. Almost no cleavage was observed upon full deletion of this domain. These results suggest that alpha-cleavage is executed by an alpha-PrPase whose activity, despite surprisingly limited sequence specificity, is dependent on the size of the central region of PrP(C).

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:26 Mar 2010 09:59
Last Modified:28 Nov 2013 00:21
Publisher:Public Library of Science
ISSN:1932-6203
Publisher DOI:10.1371/journal.pone.0009107
PubMed ID:20161712
Citations:Web of Science®. Times Cited: 18
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Scopus®. Citation Count: 17

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