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Structural basis for ligand capture and release by the endocytic receptor Apo ER 2
Author(s) -
Hirai Hidenori,
Yasui Norihisa,
Yamashita Keitaro,
Tabata Sanae,
Yamamoto Masaki,
Takagi Junichi,
Nogi Terukazu
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643521
Subject(s) - ldl receptor , ectodomain , internalization , ligand (biochemistry) , endocytosis , endocytic cycle , chemistry , receptor , biophysics , apolipoprotein b , plasma protein binding , biochemistry , microbiology and biotechnology , lipoprotein , biology , cholesterol
Apolipoprotein E receptor 2 (Apo ER 2) is a close homologue of low‐density lipoprotein receptor ( LDLR ) that mediates the endocytosis of ligands, including LDL particles. LDLR family members have been presumed to explore a large conformational space to capture ligands in the extended conformation at the cell surface. Ligands are subsequently released through a pH ‐titrated structural transition to a self‐docked, contracted‐closed conformation. In addition to lipoprotein uptake, Apo ER 2 is implicated in signal transduction during brain development through capture of the extracellular protein reelin. From crystallographic analysis, we determine that the full‐length Apo ER 2 ectodomain adopts an intermediate contracted‐open conformation when complexed with the signaling‐competent reelin fragment, and we identify a previously unappreciated auxiliary low‐affinity binding interface. Based on mutational analyses, we propose that the pH shift during endocytosis weakens the affinity of the auxiliary interface and destabilizes the ligand–receptor complex. Furthermore, this study elucidates that the contracted‐open conformation of ligand‐bound Apo ER 2 at neutral pH resembles the contracted‐closed conformation of ligand‐unbound LDLR at acidic pH in a manner suggestive of being primed for ligand release even prior to internalization.