SORTEM - SorCS neuroreceptors and how they modulate transmembrane signaling complexes.

• Applicant: Professor Dr. Arne Möller
• Subject Area: Structural Biology ; Biophysics ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412347668

Sortilins (or Vps10p-domain receptors) are type-I membrane proteins that are highly expressed in the human brain. They are hallmarked by the extracellular Vps10p-domain, which is composed of a unique ten bladed beta-propeller and a cysteine rich domain. Recently, sortilins were identified as the 3rd class of neurotrophic receptors (in addition to Trk and p75NTR), which are fundamental for neuronal development and modulation of synaptic plasticity. The signaling complex of Trk, p75NTR and a specific neurotrophin promotes growth and survival of neuronal cells. In stark contrast, assembly of sortilin p75NTR and the pro-form of a neurotrophin triggers apoptosis. With this proposal we want to understand the molecular mechanics that underlie this fundamental difference in signaling.The sortilin family comprises five members: Sortilin, SorLA and SorCS1-3. We will focus on the SorCS-subfamily, which is functionally linked to neurodegenerative disorders such as Schizophrenia, Alzheimer’s and Huntington’s disease. Intriguingly, pro-neurotrophins are not exclusive ligands for SorCS. In fact, they interact with a large and diverse range of protein ligands, which explains their additional involvement in diabetes, cancer and cardiovascular diseases. While the amount of biomedical information on SorCS, and sortilins in general, is growing rapidly, structural data remains very limited. To date, only the Vps10p-domains of sortilin and SorLA are well characterized. Structural data on SorCS, which would reveal how they modulate and transfer transmembrane signaling in conjunction with additional membrane proteins and extracellular messengers, are not available.In our project we want to provide this missing information. We will use cryo-electron microscopy to obtain a detailed picture of the structure of fully assembled SorCS signaling complexes. Our data will enable us to understand the underpinning molecular mechanisms of this class of neurotrophic receptors. The identification of ligand binding sites may enable futural development of specific therapeutics.

• DFG Programme: Research Grants