Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin

Dovile Januliene; Jacob Lauwring Andersen; Jeppe Achton Nielsen; Esben Meldgaard Quistgaard; Maria Hansen; Dorthe Strandbygaard; Arne Moeller; Claus Munck Petersen; Peder Madsen; Søren Skou Thirup

doi:10.1016/j.str.2017.09.015

Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin

Dovile Januliene, Jacob Lauwring Andersen, Jeppe Achton Nielsen, Esben Meldgaard Quistgaard, Maria Hansen, Dorthe Strandbygaard, Arne Moeller, Claus Munck Petersen, Peder Madsen, Søren Skou Thirup

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

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.

Original language	English
Article number	12
Journal	Structure
Volume	25
Issue	12
Pages (from-to)	1809-1819.e3
Number of pages	14
ISSN	0969-2126
DOIs	https://doi.org/10.1016/j.str.2017.09.015
Publication status	Published - 5 Dec 2017

Keywords

Vps10p domain
conformational change
crystal structure
dimerization
endocytosis
histidine
ligand release
sortilin
sorting

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10.1016/j.str.2017.09.015

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title = "Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin",

abstract = "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-{\AA} 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.",

keywords = "Vps10p domain, conformational change, crystal structure, dimerization, endocytosis, histidine, ligand release, sortilin, sorting",

author = "Dovile Januliene and Andersen, {Jacob Lauwring} and Nielsen, {Jeppe Achton} and Quistgaard, {Esben Meldgaard} and Maria Hansen and Dorthe Strandbygaard and Arne Moeller and Petersen, {Claus Munck} and Peder Madsen and Thirup, {S{\o}ren Skou}",

year = "2017",

month = dec,

day = "5",

doi = "10.1016/j.str.2017.09.015",

language = "English",

volume = "25",

pages = " 1809--1819.e3",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

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}

Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin. / Januliene, Dovile; Andersen, Jacob Lauwring; Nielsen, Jeppe Achton et al.
In: Structure, Vol. 25, No. 12, 12, 05.12.2017, p. 1809-1819.e3.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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

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

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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 -

Acidic Environment Induces Dimerization and Ligand Binding Site Collapse in the Vps10p Domain of Sortilin

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Keywords

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