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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.

Structural basis for ligand capture and release by the endocytic receptor Apo ER 2