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

• Published in: The Journal of biological chemistry Vol. 298; no. 3; p. 101568
• Main Authors: Conroy, Jacinta N., Coulson, Elizabeth J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2022; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; high-affinity binding; Humans; intracellular domain; JBC Reviews; nerve growth factor; Nerve Growth Factors - metabolism; neurotrophin; p75 neurotrophin receptor; Receptor Protein-Tyrosine Kinases - metabolism; receptor structure-function; receptor tyrosine kinase; Receptor, Nerve Growth Factor - metabolism; Receptor, trkA - genetics; Receptor, trkA - metabolism; Receptors, Nerve Growth Factor; transmembrane domain; Trk receptor; TrkA; Tropomyosin; intracellular domain; NT-3; RTK; Trk; receptor structure-function; EGFR; p75; Shc; PI3K; nerve growth factor; transmembrane domain; HeLa cells; GnRH; PC12 cell; NT-4/5; Trk receptor; p75 neurotrophin receptor; BDNF; MAH cells; ErbB4; ECD; high-affinity binding; Akt; c29; ICD; MAPK; NGF; EpoR; A293 cells; TrkA; ADAM10/17; SCG; RIP; Kd; TM; receptor tyrosine kinase; Grb2; neurotrophin; D1–D5; Chopper (domain); ERK
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1016/j.jbc.2022.101568

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.