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Identification of a linear epitope in sortilin that partakes in pro-neurotrophin binding

Item Type:Article
Title:Identification of a linear epitope in sortilin that partakes in pro-neurotrophin binding
Creators Name:Andersen, O.S. and Boisguerin, P. and Glerup, S. and Skeldal, S. and Volkmer, R. and Willnow, T.E. and Nykjaer, A. and Andersen, O.M.
Abstract:Sortilin acts as cell surface receptor for proneurotrophins (proNT) that upon complex formation with the p75 neurotrophin receptor (p75NTR) is able to signal neuronal cell death. Here we screened a sortilin peptide library comprising 16-mer overlapping sequences for binding of the pro-domains of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). We find that a linear surface exposed sequence, R163IFRSSDFAKNF174, constitutes an important proNT binding epitope in sortilin. Systematic mutational analysis revealed residues R163, F165, R166 and F170 to be critical for the interaction. Expression of a sortilin mutant in which these four amino acids were substituted by alanines disrupted proNT binding without affecting receptor heterodimerization with p75NTR or binding of ligands that selectively engages the centrally located tunnel in the b-propeller of sortilin. We furthermore demonstrate that a peptide comprising the ligand-binding epitope can prevent proNT-induced apoptosis in RN22 schwannoma cells.
Keywords:Growth Factors, Neuropeptide, Protein-Protein Interactions, Ligand Binding, Cell Surface Receptor, VPS10p Receptor, Pro-Neurotrophin, Sortilin
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:12210-12222
Date:16 April 2010
Official Publication:https://doi.org/10.1074/jbc.M109.062364
PubMed:View item in PubMed

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