The effects of transmembrane sequence and dimerization on cleavage of the p75 neurotrophin receptor by γ-secretase

Sykes, Alex M., Palstra, Nick, Abankwa, Daniel, Hill, Justine M., Skeldal, Sune, Matusica, Dusan, Venkatraman, Prahatha, Hancock, John F. and Coulson, Elizabeth J. (2012) The effects of transmembrane sequence and dimerization on cleavage of the p75 neurotrophin receptor by γ-secretase. Journal of Biological Chemistry, 287 52: 43810-43824. doi:10.1074/jbc.M112.382903

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Author Sykes, Alex M.
Palstra, Nick
Abankwa, Daniel
Hill, Justine M.
Skeldal, Sune
Matusica, Dusan
Venkatraman, Prahatha
Hancock, John F.
Coulson, Elizabeth J.
Title The effects of transmembrane sequence and dimerization on cleavage of the p75 neurotrophin receptor by γ-secretase
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2012-12
Sub-type Article (original research)
DOI 10.1074/jbc.M112.382903
Open Access Status File (Publisher version)
Volume 287
Issue 52
Start page 43810
End page 43824
Total pages 15
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2013
Language eng
Abstract Cleavage of transmembrane receptors by γ-secretase is the final step in the process of regulated intramembrane proteolysis (RIP) and has a significant impact on receptor function. Although relatively little is known about the molecular mechanism of γ-secretase enzymatic activity, it is becoming clear that substrate dimerization and/or the substrate's α-helical structure can regulate the site and rate of γ-secretase activtiy. Here we show that the transmembrane domain of the pan neurotrophin receptor p75NTR, best known for regulating neuronal death, is sufficient for its homodimerization. While the p75NTR ligands NGF and proNGF do not induce homerdimerization or RIP, homodimers of p75NTR are γ-secretase substrates. However dimerization is not a requirement for p75NTR cleavage, suggesting that γ-secretase has the ability to recognize and cleave each receptor molecule independently. The transmembrane cysteine 257, which mediates covalent p75NTR interactions, is not crucial for homodimerization, but this residue is required for normal rates of γ-secretase cleavage. Similarly, mutation of the residues alanine 262 and glycine 266 of an AxxxG dimerization motif flanking the γ-secretase cleavage site within the p75NTR transmembrane domain, alters the orientation of the domain and inhibits γ-secretase cleavage of p75NTR. Nonetheless, heteromer interactions of p75NTR with TrkA increase full-length p75NTR homodimerization, which in turn may potentiate the rate of γ-cleavage following TrkA activation independently of rates of α-cleavage. These results provide support for the idea that the helical structure of the p75NTR transmembrane domain, rather than dimerization, is a key element in catalyzing γ-secretase cleavage.
Keyword p75 neurotrophin receptor
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes First Published: 26 October 2012.

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Created: Fri, 23 Nov 2012, 11:48:30 EST by Debra McMurtrie on behalf of Queensland Brain Institute