High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair |
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Authors: | Jacinta N Conroy Elizabeth J Coulson |
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Institution: | 1.School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia;2.Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia;3.Clem Jones Centre for Ageing and Disease Research, The University of Queensland, Brisbane, Queensland, Australia |
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Abstract: | Neurotrophin signaling is essential for normal nervous system development and adult function. Neurotrophins are secreted proteins that signal via interacting with two neurotrophin receptor types: the multifaceted p75 neurotrophin receptor and the tropomyosin receptor kinase receptors. In vivo, neurons compete for the limited quantities of neurotrophins, a process that underpins neural plasticity, axonal targeting, and ultimately survival of the neuron. Thirty years ago, it was discovered that p75 neurotrophin receptor and tropomyosin receptor kinase A form a complex and mediate high-affinity ligand binding and survival signaling; however, despite decades of functional and structural research, the mechanism of modulation that yields this high-affinity complex remains unclear. Understanding the structure and mechanism of high-affinity receptor generation will allow development of pharmaceuticals to modulate this function for treatment of the many nervous system disorders in which altered neurotrophin expression or signaling plays a causative or contributory role. Here we re-examine the key older literature and integrate it with more recent studies on the topic of how these two receptors interact. We also identify key outstanding questions and propose a model of inside-out allosteric modulation to assist in resolving the elusive high-affinity mechanism and complex. |
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Keywords: | neurotrophin p75 neurotrophin receptor nerve growth factor TrkA Trk receptor receptor tyrosine kinase transmembrane domain intracellular domain high-affinity binding receptor structure-function |
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