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

Sune Skeldal, Alex Sykes, Simon Glerup, Dusan Matusica, Nickless Palstra, Henry Autio, Zoran Boskovic, Peder Madsen, Eero Castren, A Nykjaer, Elizabeth Coulson

    Research output: Contribution to journalArticle

    32 Citations (Scopus)

    Abstract

    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 (p75NTR). To identify the interaction site between sortilin and p75NTR, we analyzed binding between chimeric receptor constructs and truncated p75NTR variants by co-immunoprecipitation experiments, surface plasmon resonance analysis, and FRET. We found that complex formation between sortilin and p75NTR 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 p75NTR. Functional studies further revealed an important regulatory function of the sortilin intracellular domain in p75NTR-regulated intramembrane proteolysis and apoptosis. Thus, although the intracellular domain of sortilin does not contribute to p75NTR binding, it does regulate the rates of p75NTR cleavage, which is required to mediate pro-neurotrophin-stimulated cell death.

    Original languageEnglish
    Pages (from-to)43798-43809
    Number of pages12
    JournalJournal of Biological Chemistry
    Volume287
    Issue number52
    DOIs
    Publication statusPublished - 2012

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