caa a22 4500 606176756 CHVBK 20210128100749.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s00018-014-1777-y doi (NATIONALLICENCE)springer-10.1007/s00018-014-1777-y MEK1 transduces the prion protein N2 fragment antioxidant effects [Elektronische Daten] [C. Haigh, A. McGlade, S. Collins] The prion protein (PrPC) when mis-folded is causally linked with a group of fatal neurodegenerative diseases called transmissible spongiform encephalopathies or prion diseases. PrPC normal function is still incompletely defined with such investigations complicated by PrPC 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 PrPC 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 PrPC. Springer Basel, 2014 CJD nationallicence N-terminus nationallicence PrP23-89 nationallicence Beta-cleavage nationallicence Reactive oxygen species nationallicence Signal transduction nationallicence Mitogen-activated protein kinase nationallicence Haigh C. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, 3010, Melbourne, Australia aut McGlade A. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, 3010, Melbourne, Australia aut Collins S. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, 3010, Melbourne, Australia aut Cellular and Molecular Life Sciences Springer Basel 72/8(2015-04-01), 1613-1629 1420-682X 72:8<1613 2015 72 18 https://doi.org/10.1007/s00018-014-1777-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1777-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Haigh C. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, 3010, Melbourne, Australia aut NATIONALLICENCE 700 1- McGlade A. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, 3010, Melbourne, Australia aut NATIONALLICENCE 700 1- Collins S. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, 3010, Melbourne, Australia aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/8(2015-04-01), 1613-1629 1420-682X 72:8<1613 2015 72 18