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Investigating the Conformational Response of the Sortilin Receptor upon Binding Endogenous Peptide- and Protein Ligands by HDX-MS.
Trabjerg, Esben; Abu-Asad, Nadia; Wan, Ziqian; Kartberg, Fredrik; Christensen, Søren; Rand, Kasper D.
Afiliación
  • Trabjerg E; Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark; Biotherapeutic Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
  • Abu-Asad N; Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark.
  • Wan Z; Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark.
  • Kartberg F; Biotherapeutic Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
  • Christensen S; Biotherapeutic Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
  • Rand KD; Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark. Electronic address: kasper.rand@sund.ku.dk.
Structure ; 27(7): 1103-1113.e3, 2019 07 02.
Article en En | MEDLINE | ID: mdl-31104815
Sortilin is a multifunctional neuronal receptor involved in sorting of neurotrophic factors and apoptosis signaling. So far, structural characterization of sortilin and its endogenous ligands has been limited to crystallographic studies of sortilin in complex with the neuropeptide neurotensin. Here, we use hydrogen/deuterium exchange mass spectrometry to investigate the conformational response of sortilin to binding biological ligands including the peptides neurotensin and the sortilin propeptide and the proteins progranulin and pro-nerve growth factor-ß. The results show that the ligands use two binding sites inside the cavity of the ß-propeller of sortilin. However, ligands have distinct differences in their conformational impact on the receptor. Interestingly, the protein ligands induce conformational stabilization in a remote membrane-proximal domain, hinting at an unknown conformational link between the ligand binding region and this membrane-proximal region of sortilin. Our findings improve our structural understanding of sortilin and how it mediates diverse ligand-dependent functions important in neurobiology.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Precursores de Proteínas / Proteínas Recombinantes de Fusión / Neurotensina / Factor de Crecimiento Nervioso / Proteínas Adaptadoras del Transporte Vesicular / Progranulinas Tipo de estudio: Prognostic_studies Idioma: En Revista: Structure Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Precursores de Proteínas / Proteínas Recombinantes de Fusión / Neurotensina / Factor de Crecimiento Nervioso / Proteínas Adaptadoras del Transporte Vesicular / Progranulinas Tipo de estudio: Prognostic_studies Idioma: En Revista: Structure Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Estados Unidos