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

ABSTRACT: Sortilin acts as a cell surface receptor for pro-neurotrophins (pro-NT) that upon complex formation with the p75 neurotrophin receptor (p75(NTR)) 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 and brain-derived neurotrophic factor. We find that a linear surface-exposed sequence, (163)RIFRSSDFAKNF(174), constitutes an important pro-NT binding epitope in sortilin. Systematic mutational analysis revealed residues Arg(163), Phe(165), Arg(166), and Phe(170) to be critical for the interaction. Expression of a sortilin mutant in which these four amino acids were substituted by alanines disrupted pro-NT binding without affecting receptor heterodimerization with p75(NTR) or binding of ligands that selectively engages the centrally located tunnel in the beta-propeller of sortilin. We furthermore demonstrate that a peptide comprising the ligand-binding epitope can prevent pro-NT-induced apoptosis in RN22 schwannoma cells.

SUBMITTER: Serup Andersen O

PROVIDER: S-EPMC2852960 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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

Serup Andersen Olga O Boisguerin Prisca P Glerup Simon S Skeldal Sune S Volkmer Rudolf R Willnow Thomas E TE Nykjaer Anders A Andersen Olav M OM

The Journal of biological chemistry 20100216 16

Sortilin acts as a cell surface receptor for pro-neurotrophins (pro-NT) that upon complex formation with the p75 neurotrophin receptor (p75(NTR)) 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 and brain-derived neurotrophic factor. We find that a linear surface-exposed sequence, (163)RIFRSSDFAKNF(174), constitutes an important pro-NT binding epitope in sortilin. Syste ...[more]

PMID: 20159974

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Dataset Information

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

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

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