Abstract
Signaling of SorCS receptors by proneurotrophin ligands regulates neuronal plasticity, induces apoptosis and is associated with mental disorders. The detailed structure of SorCS2 and its extracellular specificity are unresolved. Here we report crystal structures of the SorCS2–NGF complex and unliganded SorCS2 ectodomain, revealing cross-braced SorCS2 homodimers with two NGF dimers bound in a 2:4 stoichiometry. Five out of six SorCS2 domains directly contribute to dimer formation and a C-terminal membrane proximal unreported domain, with an RNA recognition motif fold, locks the dimer in an intermolecular head-to-tail interaction. The complex structure shows an altered SorCS2 conformation indicating substantial structural plasticity. Both NGF dimer chains interact exclusively with the top face of a SorCS2 β-propeller. Biophysical experiments reveal that NGF, proNGF, and proBDNF bind at this site on SorCS2. Taken together, our data reveal a structurally flexible SorCS2 receptor that employs the large β-propeller as a ligand binding platform.
Highlights
Signaling of SorCS receptors by proneurotrophin ligands regulates neuronal plasticity, induces apoptosis and is associated with mental disorders
Neurotrophins, on the other hand, function as growth factors, and induce growth and survival of neurons by binding the receptors tropomyosin receptor kinase (Trk) and p75NTR7. Both proneurotrophins and neurotrophins bind to Vacuolar Protein Sorting 10 protein (VPS10p) members, p75 neurotrophic receptor (p75NTR) and Trk, but in general the affinity of proneurotrophin is higher for VPS10p members while that of neurotrophins is higher for p75NTR and Trk[4,6], there is one exception; NGF binds with higher affinity to SorCS3 than does proNGF20
The cross-braced homodimer architecture and the domain composition of the VPS10p subunit followed by two polycystic kidney disease (PKD) domains and a SoMP domain is predicted to be conserved among the three SorCS members
Summary
Signaling of SorCS receptors by proneurotrophin ligands regulates neuronal plasticity, induces apoptosis and is associated with mental disorders. No high-resolution information is available for the VPS10p subunit of any SorCS member and the details of SorCS dimerization are unresolved Proneurotrophins and their proteolytic processed mature forms, neurotrophins, have predominantly distinct functions. Proneurotrophins, such as pro-nerve growth factor (proNGF) and pro-brain-derived neurotropic factor (proBDNF), can trigger neuronal apoptosis, growth cone retraction, and regulate neuronal plasticity by forming a ternary complex with VPS10p members SorCS2 or Sortilin and the p75 neurotrophic receptor (p75NTR)[3,4,5,6]. How proneurotrophins interact with SorCS2 or other VPS10p members is not well understood but structures of NGF and proNGF in complex with p75NTR12,22 and of NGF in complex with Trk[23,24] have revealed how NGF and proNGF homodimers engage the p75NTR and Trk receptors via an overlapping binding site on the mature domain of NGF. The pro domain of neurotrophins is largely disordered[26,27] and was not resolved in the crystal structure of the proNGF–p75NTR complex[12]
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