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Dominant roles of the polybasic proline motif and copper in the PrP23-89-mediated stress protection response
- Source :
- Journal of Cell Science. 122:1518-1528
- Publication Year :
- 2009
- Publisher :
- The Company of Biologists, 2009.
-
Abstract
- Beta-cleavage of the neurodegenerative disease-associated prion protein (PrP) protects cells from death induced by oxidative insults. The beta-cleavage event produces two fragments, designated N2 and C2. We investigated the role of the N2 fragment (residues 23-89) in cellular stress response, determining mechanisms involved and regions important for this reaction. The N2 fragment differentially modulated the reactive oxygen species (ROS) response induced by serum deprivation, with amelioration when copper bound. Amino acid residues 23-50 alone mediated a ROS reduction response. PrP23-50 ROS reduction was not due to copper binding or direct antioxidant activity, but was instead mediated through proteoglycan binding partners localised in or interacting with cholesterol-rich membrane domains. Furthermore, mutational analyses of both PrP23-50 and N2 showed that their protective capacity requires the sterically constraining double proline motif within the N-terminal polybasic region. Our findings show that N2 is a biologically active fragment that is able to modulate stress-induced intracellular ROS through interaction of its structurally defined N-terminal polybasic region with cell-surface proteoglycans.
- Subjects :
- Time Factors
Proline
Protein Conformation
Amino Acid Motifs
Cell Line
Superoxide dismutase
Mice
Structure-Activity Relationship
Membrane Microdomains
Protein structure
Cellular stress response
Animals
PrPC Proteins
Binding site
Neurons
chemistry.chemical_classification
Binding Sites
biology
Proteoglycan binding
Cell Biology
Endocytosis
Peptide Fragments
Protein Structure, Tertiary
Cell biology
Amino acid
Oxidative Stress
Cholesterol
Biochemistry
chemistry
Cytoprotection
Mutation
biology.protein
Signal transduction
Reactive Oxygen Species
Copper
Heparan Sulfate Proteoglycans
Intracellular
Half-Life
Subjects
Details
- ISSN :
- 14779137 and 00219533
- Volume :
- 122
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....d019a71bf08f71794e6d739d948d73fa
- Full Text :
- https://doi.org/10.1242/jcs.043604