Abstract
SummaryEvents at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms (TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligands NT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways, whereas PTP-sigma activates biased signals. Our data support an “in-to-out” model controlling receptor ectodomain conformation, a strategy that enables heterogeneity in receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.
Highlights
The TrkC receptor is a key player in the development, selection, maintenance, health, phenotype, and function of motor neurons, vascular endothelium, and other cell types (Saragovi et al, 2009; Segal, 2003; Sendtner et al, 1996; Youn et al, 2003)
Immunohistochemistry (Figure 1B) and flow cytometry (Figure 1C) studies show that monoclonal antibodies (mAbs) 1E11 is preferentially selective for the TrkC.T1 ectodomain
The mAb 2B7 epitope is at the linker region between D5 domain and the transmembrane domain, adjacent to D5 (Guillemard et al, 2010), the domain where NT-3 binds (Urfer et al, 1998)
Summary
The TrkC receptor is a key player in the development, selection, maintenance, health, phenotype, and function of motor neurons, vascular endothelium, and other cell types (Saragovi et al, 2009; Segal, 2003; Sendtner et al, 1996; Youn et al, 2003). The trkC mRNA splicing event changes the primary sequence of the intracellular domain, but the juxtamembrane, the transmembrane, and the ectodomain primary sequences remain identical (Esteban et al, 2006). Both TrkC-FL and TrkC.T1 are naturally occurring, but their expression patterns differ in health and in disease, and more importantly the isoforms transduce opposite signals. TrkC-FL is expressed throughout life, and the tyrosine kinase signals are key to maintaining motor neuron health, phenotype, and function (Deinhardt and Chao, 2014). TrkC.T1 plays a deleterious role by stimulating overproduction of TNF-a to neurotoxic levels, contributing to disease onset and progression (Bai et al, 2010; Brahimi et al, 2016; Dorsey et al, 2006; Galan et al, 2017; Yanpallewar et al, 2012)
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