TY - JOUR
T1 - Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin
AU - Januliene, Dovile
AU - Andersen, Jacob Lauwring
AU - Nielsen, Jeppe Achton
AU - Quistgaard, Esben Meldgaard
AU - Hansen, Maria
AU - Strandbygaard, Dorthe
AU - Moeller, Arne
AU - Petersen, Claus Munck
AU - Madsen, Peder
AU - Thirup, Søren Skou
N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.
PY - 2017/12/5
Y1 - 2017/12/5
N2 - Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-Å resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released. The structure reveals an overall distortion of the 10-bladed β-propeller domain. This distortion and specific conformational changes, caused by protonation of a number of histidine residues, render the currently known binding sites unavailable for ligand binding. Access to the binding sites is furthermore blocked by a reversible and pH-dependent formation of tight sortilin dimers, also confirmed by electron microscopy, size-exclusion chromatography, and mutational studies. This study reveals how sortilin binding sites are disrupted and explains pH-dependent ligand affinity.
AB - Sortilin is a neuronal receptor involved in transmembrane signaling, endocytosis, and intracellular sorting of proteins. It cycles through a number of cellular compartments where it encounters various acidic conditions. The crystal structure of the sortilin ectodomain has previously been determined at neutral pH. Here, we present the 3.5-Å resolution crystal structure of sortilin at pH 5.5, which represents an environment similar to that of late endosomes, where ligands are released. The structure reveals an overall distortion of the 10-bladed β-propeller domain. This distortion and specific conformational changes, caused by protonation of a number of histidine residues, render the currently known binding sites unavailable for ligand binding. Access to the binding sites is furthermore blocked by a reversible and pH-dependent formation of tight sortilin dimers, also confirmed by electron microscopy, size-exclusion chromatography, and mutational studies. This study reveals how sortilin binding sites are disrupted and explains pH-dependent ligand affinity.
KW - Vps10p domain
KW - conformational change
KW - crystal structure
KW - dimerization
KW - endocytosis
KW - histidine
KW - ligand release
KW - sortilin
KW - sorting
UR - http://www.scopus.com/inward/record.url?scp=85032576095&partnerID=8YFLogxK
U2 - 10.1016/j.str.2017.09.015
DO - 10.1016/j.str.2017.09.015
M3 - Journal article
C2 - 29107483
SN - 0969-2126
VL - 25
SP - 1809-1819.e3
JO - Structure
JF - Structure
IS - 12
M1 - 12
ER -