Investigating the Conformational Response of the Sortilin Receptor upon Binding Endogenous Peptide- and Protein Ligands by HDX-MS
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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.
In: Structure, Vol. 27, No. 7, 02.07.2019, p. 1103-1113.e3.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
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
VL - 27
SP - 1103-1113.e3
JO - Structure
JF - Structure
SN - 0969-2126
IS - 7
ER -
ID: 228973685