A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling.

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS2 intracellular domain (ICD) contains a triple serine motif that potentially functions as a signaling switch to induce intracellular signaling in hippocampal neurons. We show, that serine to alanine substitution in this motif renders neurons less responsive to BDNF, whereas phosphomimetic mutations induce neurotrophic effects independently of the SorCS2 extracellular domain (ECD) and BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate distinct intracellular signaling, partially overlapping with the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide insights into SorCS2 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active molecules.