Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers

Marçal Vilar; Ioannis Charalampopoulos; Rajappa S. Kenchappa; Anastasia Simi; Esra Karaca; Alessandra Reversi; Soyoung Choi; Mark Bothwell; Ismael Mingarro; Wilma J. Friedman; Giampietro Schiavo; Philippe I.H. Bastiaens; Peter J. Verveer; Bruce D. Carter; Carlos F. Ibáñez

doi:10.1016/j.neuron.2009.02.020

Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers

Marçal Vilar, Ioannis Charalampopoulos, Rajappa S. Kenchappa, Anastasia Simi, Esra Karaca, Alessandra Reversi, Soyoung Choi, Mark Bothwell, Ismael Mingarro, Wilma J. Friedman, Giampietro Schiavo, Philippe I.H. Bastiaens, Peter J. Verveer, Bruce D. Carter, Carlos F. Ibáñez

Cancer Biology

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107 Scopus citations

Abstract

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75^NTR), but the mechanism of receptor activation has remained elusive. Here, we show that p75^NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys²⁵⁷ in its transmembrane domain. Mutation of Cys²⁵⁷ abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75^NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75^NTR. FRET experiments revealed a close association of p75^NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys²⁵⁷ did not alter the oligomeric state of p75^NTR, the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75^NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.

Original language	English (US)
Pages (from-to)	72-83
Number of pages	12
Journal	Neuron
Volume	62
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2009.02.020
State	Published - Apr 16 2009

Keywords

MOLNEURO
PROTEINS
SIGNALING

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2009.02.020

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Vilar, M., Charalampopoulos, I., Kenchappa, R. S., Simi, A., Karaca, E., Reversi, A., Choi, S., Bothwell, M., Mingarro, I., Friedman, W. J., Schiavo, G., Bastiaens, P. I. H., Verveer, P. J., Carter, B. D., & Ibáñez, C. F. (2009). Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers. Neuron, 62(1), 72-83. https://doi.org/10.1016/j.neuron.2009.02.020

Vilar, M, Charalampopoulos, I, Kenchappa, RS, Simi, A, Karaca, E, Reversi, A, Choi, S, Bothwell, M, Mingarro, I, Friedman, WJ, Schiavo, G, Bastiaens, PIH, Verveer, PJ, Carter, BD & Ibáñez, CF 2009, 'Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers', Neuron, vol. 62, no. 1, pp. 72-83. https://doi.org/10.1016/j.neuron.2009.02.020

@article{ff061fbcb1fb4e9190546796d070fb89,

title = "Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers",

abstract = "Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the mechanism of receptor activation has remained elusive. Here, we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75NTR. FRET experiments revealed a close association of p75NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys257 did not alter the oligomeric state of p75NTR, the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.",

keywords = "MOLNEURO, PROTEINS, SIGNALING",

author = "Mar{\c c}al Vilar and Ioannis Charalampopoulos and Kenchappa, {Rajappa S.} and Anastasia Simi and Esra Karaca and Alessandra Reversi and Soyoung Choi and Mark Bothwell and Ismael Mingarro and Friedman, {Wilma J.} and Giampietro Schiavo and Bastiaens, {Philippe I.H.} and Verveer, {Peter J.} and Carter, {Bruce D.} and Ib{\'a}{\~n}ez, {Carlos F.}",

note = "Funding Information: We thank Phil Barker for MC192 antibody; Moses Chao, Toshihide Yamashita, Anders Nykj{\ae}r, and Daniel Lee for RIP2, RhoGDI, sortilin, and Lingo-1 expression plasmids; and Neil McDonald for fruitful discussions. This work was supported by grants from the Swedish Foundation for Strategic Research (CEDB), the Swedish Research Council (33X-10908-10A and Linn{\'e} program), the Vth Framework Program of the European Union (QLG3-CT-1999-00573), and the National Institutes of Health (NIH 1 R01 MH071624-01A2). R.S.K. and B.D.C. were supported by the National Institutes of Health (R01 NS038220), A.R. and G.S. by Cancer Research UK, M.B. by the National Institutes of Health (NIH 5 R01NS47348), I.M. by the Spanish Ministry of Education (BFU2006-08542), and A.S by the Marie Curie RTN “ENDOCYTE” from the European Union FP6 Program.",

year = "2009",

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day = "16",

doi = "10.1016/j.neuron.2009.02.020",

language = "English (US)",

volume = "62",

pages = "72--83",

journal = "Neuron",

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T1 - Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers

AU - Vilar, Marçal

AU - Charalampopoulos, Ioannis

AU - Kenchappa, Rajappa S.

AU - Simi, Anastasia

AU - Karaca, Esra

AU - Reversi, Alessandra

AU - Choi, Soyoung

AU - Bothwell, Mark

AU - Mingarro, Ismael

AU - Friedman, Wilma J.

AU - Schiavo, Giampietro

AU - Bastiaens, Philippe I.H.

AU - Verveer, Peter J.

AU - Carter, Bruce D.

AU - Ibáñez, Carlos F.

N1 - Funding Information: We thank Phil Barker for MC192 antibody; Moses Chao, Toshihide Yamashita, Anders Nykjær, and Daniel Lee for RIP2, RhoGDI, sortilin, and Lingo-1 expression plasmids; and Neil McDonald for fruitful discussions. This work was supported by grants from the Swedish Foundation for Strategic Research (CEDB), the Swedish Research Council (33X-10908-10A and Linné program), the Vth Framework Program of the European Union (QLG3-CT-1999-00573), and the National Institutes of Health (NIH 1 R01 MH071624-01A2). R.S.K. and B.D.C. were supported by the National Institutes of Health (R01 NS038220), A.R. and G.S. by Cancer Research UK, M.B. by the National Institutes of Health (NIH 5 R01NS47348), I.M. by the Spanish Ministry of Education (BFU2006-08542), and A.S by the Marie Curie RTN “ENDOCYTE” from the European Union FP6 Program.

PY - 2009/4/16

Y1 - 2009/4/16

N2 - Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the mechanism of receptor activation has remained elusive. Here, we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75NTR. FRET experiments revealed a close association of p75NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys257 did not alter the oligomeric state of p75NTR, the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.

AB - Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the mechanism of receptor activation has remained elusive. Here, we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75NTR. FRET experiments revealed a close association of p75NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys257 did not alter the oligomeric state of p75NTR, the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.

KW - MOLNEURO

KW - PROTEINS

KW - SIGNALING

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Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers

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Keywords

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