Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584 CH, Utrecht, The Netherlands.
Biomolecular Mass Spectrometry & Proteomics and Netherlands Proteomics Center, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CH, Utrecht, The Netherlands.
Nat Commun. 2017 Nov 22;8(1):1708. doi: 10.1038/s41467-017-01485-5.
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.
低 pH 值诱导的配体释放和受体回收是内吞作用的重要步骤。跨膜蛋白 sortilin 是一种含有β-螺旋桨的内吞受体，可内化多种在细胞分化和稳态中起作用的配体。pH 介导的配体释放和 sortilin 回收的分子机制尚未解决。本文介绍了 sortilin 腔段（s-sortilin）在低 pH 值下发生构象变化并二聚化的晶体结构。所有三个 sortilin 腔结构域内的构象变化提供了一个改变的表面，二聚体在屏蔽大界面的同时使两个 s-sortilin C 末端紧密接近。生物物理和基于细胞的测定表明，两种不同配体家族（前神经生长因子和神经降压素）的成员优先结合 sortilin 单体。这表明 sortilin 二聚化和构象变化会释放配体并触发回收。更普遍地说，这项工作可能揭示了内吞受体诱导的低 pH 值配体释放的双重机制。
