TITLE

MEK1 transduces the prion protein N2 fragment antioxidant effects

AUTHOR(S)
Haigh, C.; McGlade, A.; Collins, S.
PUB. DATE
April 2015
SOURCE
Cellular & Molecular Life Sciences;Apr2015, Vol. 72 Issue 8, p1613
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
The prion protein (PrP) when mis-folded is causally linked with a group of fatal neurodegenerative diseases called transmissible spongiform encephalopathies or prion diseases. PrP normal function is still incompletely defined with such investigations complicated by PrP post-translational modifications, such as internal cleavage, which feasibly could change, activate, or deactivate the function of this protein. Oxidative stress induces β-cleavage and the N-terminal product of this cleavage event, N2, demonstrates a cellular protective response against oxidative stress. The mechanisms by which N2 mediates cellular antioxidant protection were investigated within an in vitro cell model. N2 protection was regulated by copper binding to the octarepeat domain, directing the route of internalisation, which stimulated MEK1 signalling. Precise membrane interactions of N2, determined by copper saturation, and involving both the copper-co-ordinating octarepeat region and the structure conferred upon the N-terminal polybasic region by the proline motif, were essential for the correct engagement of this pathway. The phenomenon of PrP post-translational modification, such as cleavage and copper co-ordination, as a molecular 'switch' for activation or deactivation of certain functions provides new insight into the apparent multi-functionality of PrP.
ACCESSION #
101642184

 

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