High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair

Neurotrophin signaling is essential for normal nervous system development and adult function. Neurotrophins are secreted proteins that signal via interacting with two neuro-trophin receptor types: the multifaceted p75 neurotrophin re-ceptor 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 de-cades 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 phar-maceuticals 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 re-ceptors 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.

Automated summary

Neurotrophin signaling is crucial for normal nervous system development and function. Understanding the mechanism of high-affinity receptor generation will facilitate the development of pharmaceuticals for the treatment of nervous system disorders. Despite decades of research, the modulation mechanism of the high-affinity complex remains unclear.