Dominant roles of the polybasic proline motif and copper in the PrP23-89-mediated stress protection response
| Autor: | Victoria A. Lawson, Cathryn L. Haigh, Colin L. Masters, Kevin J. Barnham, Steven J. Collins, Simon C. Drew, Martin Boland |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
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 |
| Zdroj: | Journal of Cell Science. 122:1518-1528 |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.043604 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|