Activation of neurotrophin signalling with light-inducible receptor tyrosine kinases

Optogenetics combined with protein engineering based on natural light-sensitive dimerizing proteins has evolved as a powerful strategy to study cellular functions. The present study focused on tropomyosin kinase receptors (Trks) that have been engineered to be light-sensitive. Trk belongs to the superfamily of receptor tyrosine kinases (RTKs), which are single-pass transmembrane receptors that are activated by natural ligands and serve crucial roles in cellular growth, differentiation, metabolism and motility. However, functional variations exist among receptors fused with light-sensitive proteins. The present study proposed a signal transduction model for light-induced receptor activation. This model is based on analysis of previous light-induced Trk receptors reported to date and comparisons to the activation mechanism of natural receptors. In this model, quantitative differences on the dimerization induced from either top-to-bottom or bottom-to-up may lead to the varying amplitude of intracellular signals. We hypothesize that the top-to-bottom propagation is more favourable for activation and yields better results compared with the bottom-to-top direction. The careful delineation of the dimerization mechanisms fine-tuning activation will guide future design for an optimum cellular output with the precision of light.