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

Skeldal, Sune, Sykes, Alex M., Glerup, Simon, Matusica, Dusan, Palstra, Nickless, Autio, Henri, Boskovic, Zoran, Madsen, Peder, Castrén, Eero, Nykjaer, Anders and Coulson, Elizabeth 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, 287 52: 43798-43809. doi:10.1074/jbc.M112.374710

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Author Skeldal, Sune
Sykes, Alex M.
Glerup, Simon
Matusica, Dusan
Palstra, Nickless
Autio, Henri
Boskovic, Zoran
Madsen, Peder
Castrén, Eero
Nykjaer, Anders
Coulson, Elizabeth J.
Title 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 name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2012-10-26
Sub-type Article (original research)
DOI 10.1074/jbc.M112.374710
Open Access Status File (Publisher version)
Volume 287
Issue 52
Start page 43798
End page 43809
Total pages 12
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2013
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Online ahead of print first published: 26 October 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2013 Collection
 
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Created: Fri, 23 Nov 2012, 11:19:56 EST by Debra McMurtrie on behalf of Queensland Brain Institute