Investigating the Conformational Response of the Sortilin Receptor upon Binding Endogenous Peptide- and Protein Ligands by HDX-MS

TY - JOUR

T1 - Investigating the Conformational Response of the Sortilin Receptor upon Binding Endogenous Peptide- and Protein Ligands by HDX-MS

AU - Trabjerg, Esben

AU - Abu-Asad, Nadia

AU - Wan, Ziqian

AU - Kartberg, Fredrik

AU - Christensen, Søren

AU - Rand, Kasper D

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/7/2

Y1 - 2019/7/2

N2 - 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-β. The results show that the ligands use two binding sites inside the cavity of the β-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.

AB - 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-β. The results show that the ligands use two binding sites inside the cavity of the β-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.

U2 - 10.1016/j.str.2019.04.006

DO - 10.1016/j.str.2019.04.006

M3 - Journal article

C2 - 31104815

SN - 0969-2126

VL - 27

SP - 1103-1113.e3

JO - Structure

JF - Structure

IS - 7

ER -