p75 Co-receptors regulate ligand-dependent and ligand-independent Trk receptor activation, in part by altering Trk docking subdomains.
Neurotrophins signal via Trk tyrosine kinase receptors and a common receptor called p75. Nerve growth factor is the cognate ligand for TrkA, brain-derived neurotrophic factor for TrkB, and neurotrophin-3 (NT-3) for TrkC. NT-3 also binds TrkA and TrkB as a heterologous ligand. All neurotrophins bind p75, which regulates ligand affinity and Trk signals. Trk extracellular domain has five subdomains: a leucine-rich motif, two cysteine-rich clusters, and immunoglobulin-like subdomains IgG-C1 and IgG-C2. The IgG-C1 subdomain is surface exposed in the tertiary structure and regulates ligand-independent activation. The IgG-C2 subdomain is less exposed but regulates cognate ligand binding and Trk activation. NT-3 as a heterologous ligand of TrkA and TrkB optimally requires the IgG-C2 but also binds other subdomains of these receptors. When p75 is co-expressed, major changes are observed; NGF-TrkA activation can occur also via the cysteine 1 subdomain, and brain-derived neurotrophic factor-TrkB activation requires the TrkB leucine-rich motif and cysteine 2 subdomains. We propose a two-site model of Trk binding and activation, regulated conformationally by the IgG-C1 subdomain. Moreover, p75 affects Trk subdomain utilization in ligand-dependent activation, possibly by conformational or allosteric control.
Zaccaro
M C
MC
Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.
Ivanisevic
L
L
Perez
P
P
Meakin
S O
SO
Saragovi
H U
HU
D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008024:Ligands; D020932:Nerve Growth Factor / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000737:chemistry* / Q000378:metabolism; D020813:Receptor, trkB / Q000737:chemistry* / Q000378:metabolism; D020812:Receptor, trkC / Q000737:chemistry* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D007074:Immunoglobulin G; D008024:Ligands; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC