Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers.

6533b871fe1ef96bd12d0eef

RESEARCH PRODUCT

Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers.

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

subject

Protein Conformation Mutant Neurones Receptor Nerve Growth Factor Mice Protein structure Chlorocebus aethiops Nerve Growth Factor Low-affinity nerve growth factor receptor RNA Small Interfering Receptor skin and connective tissue diseases Receptors neurals Cells Cultured Neurons Cell Death General Neuroscience NF-kappa B Cell biology Transmembrane domain SIGNALING Oligopeptides Neurotrophin Protein Binding Signal Transduction musculoskeletal diseases PROTEINS Neuroscience(all)Green Fluorescent Proteins Nerve Tissue Proteins Receptors Nerve Growth Factor Superior Cervical Ganglion Biology Transfection MOLNEURO Article Growth factor receptor Animals Humans Protein Interaction Domains and Motifs Receptors Growth Factor Cysteine Binding Sites Membrane Proteins biological factors Rats nervous system Animals Newborn Neurotrophin binding Mutation biology.protein sense organs Protein Multimerization rhoA GTP-Binding Protein Proteïnes

description

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Recent structural studies have shown that neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the actual 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 novel mechanism involving rearrangement of disulphide-linked receptor subunits.

year	journal	country	edition	language
2009-04-01	Neuron

10.1016/j.neuron.2009.02.020 https://pubmed.ncbi.nlm.nih.gov/19376060