Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release

Nadia Leloup,Dimphna H Meijer,Bert J C Janssen,Albert J R Heck,Martha Brennich,Dominique M E Thies-Weesie,Philip Lössl

doi:10.1038/s41467-017-01485-5

Nadia Leloup, Dimphna H Meijer + Show 5 more

Open Access

https://doi.org/10.1038/s41467-017-01485-5

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Abstract

Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a β-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. The molecular mechanisms of pH-mediated ligand release and sortilin recycling are unresolved. Here we present crystal structures that show the sortilin luminal segment (s-sortilin) undergoes a conformational change and dimerizes at low pH. The conformational change, within all three sortilin luminal domains, provides an altered surface and the dimers sterically shield a large interface while bringing the two s-sortilin C-termini into close proximity. Biophysical and cell-based assays show that members of two different ligand families, (pro)neurotrophins and neurotensin, preferentially bind the sortilin monomer. This indicates that sortilin dimerization and conformational change discharges ligands and triggers recycling. More generally, this work may reveal a double mechanism for low pH-induced ligand release by endocytosis receptors.

Highlights

Low pH-induced ligand release and receptor recycling are important steps for endocytosis
For the low-density lipoprotein (LDL) endocytosis receptor it has been shown that an intramolecular conformational rearrangement of domains discharges ligands[1] but whether such a conformational change mechanism applies to other endocytosis receptors is not clear[2]
For the LDL endocytosis receptor a low pH-induced conformational change consisting of domain rearrangements of the luminal segment discharges ligands[1]

Summary

Introduction

Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a β-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. Biophysical and cell-based assays show that members of two different ligand families, (pro) neurotrophins and neurotensin, preferentially bind the sortilin monomer. This indicates that sortilin dimerization and conformational change discharges ligands and triggers recycling. For the low-density lipoprotein (LDL) endocytosis receptor it has been shown that an intramolecular conformational rearrangement of domains discharges ligands[1] but whether such a conformational change mechanism applies to other endocytosis receptors is not clear[2]. It harbors sorting motifs that can be recognized and bound by adaptor proteins such as the clathrin adaptors Golgi-localized, γ-ear containing, Arf binding proteins 1-3 (GGA1-3), thereby mediating sortilin endocytosis and shuttling

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