Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis
| Autor: | Henri Autio, Peder Madsen, Simon Glerup, Elizabeth J. Coulson, Dusan Matusica, Eero Castrén, Anders Nykjaer, Alex M. Sykes, Sune Skeldal, Zoran Boskovic, Nickless Palstra |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
musculoskeletal diseases
Programmed cell death Recombinant Fusion Proteins Proteolysis Apoptosis Nerve Tissue Proteins Receptors Nerve Growth Factor Tropomyosin receptor kinase A Peptide Mapping Biochemistry 03 medical and health sciences 0302 clinical medicine Neurobiology Cell Line Tumor Extracellular medicine Animals Humans Low-affinity nerve growth factor receptor Receptor skin and connective tissue diseases Molecular Biology 030304 developmental biology 0303 health sciences medicine.diagnostic_test biology HEK 293 cells Cell Biology Surface Plasmon Resonance biological factors Protein Structure Tertiary Rats Cell biology Adaptor Proteins Vesicular Transport HEK293 Cells nervous system biology.protein sense organs 030217 neurology & neurosurgery Neurotrophin |
| Zdroj: | Skeldal, S, Sykes, A M, Glerup, S, Matusica, D, Palstra, N, Autio, H, Boskovic, Z, Madsen, P, Castrén, E, Nykjaer, A & Coulson, E J 2012, ' Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis ', Journal of Biological Chemistry, vol. 287, no. 52, pp. 43798-809 . https://doi.org/10.1074/jbc.M112.374710 |
| Popis: | Neurotrophins comprise a group of neuronal growth factors that are essential for the development and maintenance of the nervous system. However, the immature pro-neurotrophins promote apoptosis by engaging in a complex with sortilin and the p75 neurotrophin receptor (p75(NTR)). To identify the interaction site between sortilin and p75(NTR), we analyzed binding between chimeric receptor constructs and truncated p75(NTR) variants by co-immunoprecipitation experiments, surface plasmon resonance analysis, and FRET. We found that complex formation between sortilin and p75(NTR) relies on contact points in the extracellular domains of the receptors. We also determined that the interaction critically depends on an extracellular juxtamembrane 23-amino acid sequence of p75(NTR). Functional studies further revealed an important regulatory function of the sortilin intracellular domain in p75(NTR)-regulated intramembrane proteolysis and apoptosis. Thus, although the intracellular domain of sortilin does not contribute to p75(NTR) binding, it does regulate the rates of p75(NTR) cleavage, which is required to mediate pro-neurotrophin-stimulated cell death. |
| Databáze: | OpenAIRE |
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