MEK1 transduces the prion protein N2 fragment antioxidant effects.
The prion protein (PrP(C)) when mis-folded is causally linked with a group of fatal neurodegenerative diseases called transmissible spongiform encephalopathies or prion diseases. PrP(C) normal function is still incompletely defined with such investigations complicated by PrP(C) 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(C) 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(C).
Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, Melbourne, 3010, Australia, chaigh@unimelb.edu.au.
C L
CL
Haigh
A R
AR
McGlade
S J
SJ
Collins
D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017474:Receptors, Laminin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000975:Antioxidants; D010455:Peptides; D018621:PrPC Proteins; D011328:Prions; D017382:Reactive Oxygen Species; D017474:Receptors, Laminin; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1