Structural insights into SorCS2–Nerve Growth Factor complex formation

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.

Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function

“…Functions of p75 NTR and TrkB are influenced by two co-receptors—sortilin and SorCS2—membrane proteins that are members of the VPS10p-domain protein family. The preferential interaction of proneurotrophins with p75 NTR is dependent on association of p75 NTR with sortilin or SorCS2 9, 22 , which make binding contacts with the neurotrophin pro-domains 23 . Such interactions also mediate sortilin-dependent intracellular sorting of pro-BDNF into the regulated secretory pathway 24 and mediate p75 NTR -dependent disassembly of hippocampal dendritic spines elicited by secreted cleaved BDNF pro-domain 12 .…”

Non-Canonical Binding of a Small Molecule to Sortilin Alters Cellular Trafficking of ApoB and PCSK9 in Liver Derived Cells

“…Implications of these studies may also have impact on understanding other Sortilin related processes including insulin secretion 8,24,43 , Glut4 transport [44][45][46][47] , and plaque formation in Alzheimer's [48][49][50] as well as serving as a model for function of other Vps10 homologues such as Vth1, Vth2, and YN94 or Sortilin homologues such as SORCS and SORLA involved in similar processes as Sortilin. Understanding and delineating these protein functions should improve our understanding of the complex regulation of proteins involved in Vps10 family sorting pathways 51,52 .…”

Structural Perspectives on Extracellular Recognition and Conformational Changes of Several Type-I Transmembrane Receptors

“…One of the roles of these additional domains is to modulate binding to the VPS10 platform. For example, SorCS2 has been shown to exist in at least two different conformations (Januliene et al, 2017b ; Leloup et al, 2018 ), in one of which ligand binding is rendered impossible by the close proximity of the ligand-binding β-propeller top face to the cell membrane ( Figure 4B ).…”

“…A variation on this theme is provided by the SorCS2 receptor dimer that is pre-associated with the co-receptor p75NTR. Proneurotrophin ligand binding to SorCS2 and p75NTR may separate the two receptors (Leloup et al, 2018 ) to trigger the dissociation of the guanine nucleotide exchange factor Trio from the cytosolic side of the SorCS2-p75NTR complex and subsequent signaling (Deinhardt et al, 2011 ). Whether this pre-association mechanism is essential for receptors to respond rapidly to ligand binding has, however, not been established experimentally.…”

“…Structural biology techniques have provided detailed insights into the molecular mechanisms controlling adhesion and intercellular signaling. Structures of extracellular segments of type-I transmembrane proteins in isolation or in complexes show how these proteins interact in cis and in trans and how they can undergo conformational changes to become activated (Ferguson et al, 2003 ; Leloup et al, 2017 , 2018 ; Barak et al, 2019 ). Most of the structural data has been obtained by X-ray diffraction studies from protein crystals, but also from NMR and cryo-electron microscopy experiments.…”