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

• Final Report Year: 2022

Final Report Abstract

How type I signaling complexes transmit signals through the lipid bilayer remains an open question. In this proposal we aimed to analyze the formation of such signaling complexes using members of the sortilin family as specimen. Sortilins are hallmarked by their VPS10p domain, a ten-bladed extracellular beta-propeller that establishes the key-binding interface for extracellular ligands. The sortilin family consists of five members : Sortiln, SorLA and SorCS 1-3. In our project we put emphasis on the understudied SorCS receptors which play key roles in neuronal development but also constitute binding partners for other proteins, the insulin receptor for example. In SorCS mediated signaling, typically an extracellular messenger binds to SorCS which chaperones another type-I membrane receptor (e.g. the insulin receptor or several neuroreceptors). Generation of such ternary complexes than leads to an amplification of the signal. Aside from signalling, sortilins act as sorting receptors shuttling various proteins through the cell and guiding their correct placement. The role in sorting is far better documented than their action in signaling complexes. Using cryoEM we aimed to obtain high-resolution structures of SorCS signaling complexes. As such, in collaboration with Prof Anders Nykjaer, we could clearly reveal a direct interaction of SorCS1 with the Insulin receptor, however were so far unable to reveal the structure of this complex by cryoEM.

Publications

• Conformation space of a heterodimeric ABC exporter under turnover conditions. Nature, 571(7766), 580-583.
  Hofmann, Susanne; Januliene, Dovile; Mehdipour, Ahmad R.; Thomas, Christoph; Stefan, Erich; Brüchert, Stefan; Kuhn, Benedikt T.; Geertsma, Eric R.; Hummer, Gerhard; Tampé, Robert & Moeller, Arne
  
• Structure and autoregulation of a P4-ATPase lipid flippase. Nature, 571(7765), 366-370.
  Timcenko, Milena; Lyons, Joseph A.; Januliene, Dovile; Ulstrup, Jakob J.; Dieudonné, Thibaud; Montigny, Cédric; Ash, Miriam-Rose; Karlsen, Jesper Lykkegaard; Boesen, Thomas; Kühlbrandt, Werner; Lenoir, Guillaume; Moeller, Arne & Nissen, Poul
  
• Cryo‐EM of ABC transporters: an ice‐cold solution to everything?. FEBS Letters, 594(23), 3776-3789.
  Januliene, Dovile & Moeller, Arne
  
• Neue Möglichkeiten für die Strukturbestimmung von Membranproteinen. BIOspektrum, 26(6), 615-617.
  Gewering, Theresa & Möller, Arne
  
• Soluble SorCS1 binds the insulin receptor to enhance insulin sensitivity. Cold Spring Harbor Laboratory.
  Kjolby, Mads; Breining, Peter; Pedersen, Karen Marie; Wellner, Niels; Juul, Sørensen Karen Marie; Prior, Gjesing Anette Marianne; Januliene, Dovile; Vittrup, Dorthe Maria; Manavalan, Arulmani; Rotman, Maarten; Thotakura, Gangadaar; Hermey, Guido; Madsen, Peder; Vaegter, Christian B.; Thirup, Søren; Asplund, Olof; Prasad, Rashmi B.; Parlevliet, Edwin T.; Rensen, Patrick C.N. ... & Nykjaer, Anders
  
• Single-Particle Cryo-EM of Membrane Proteins. Methods in Molecular Biology, 153-178. Springer US.
  Januliene, Dovile & Moeller, Arne
  
• Frozen motion: how cryo-EM changes the way we look at ABC transporters. Trends in Biochemical Sciences, 47(2), 136-148.
  Shvarev, Dmitry; Januliene, Dovile & Moeller, Arne