Extracellular and intracellular associations of LRP with membrane-bound ligands. Left panel: Internalization of GPI-linked or heparan sulfate proteoglycan–linked (HSPG-linked) ligands (examples: uPA:PAI-1, uPA receptor, and apoE-containing lipoproteins). In uPA:PAI-1, PAI-1 binds to LRP and uPA binds to the GPI-linked uPA receptor. ApoE-containing lipoproteins are sequestered on HSPGs, facilitating enrichment with apoE and the interaction with LRP. After internalization and dissociation of the ligands from the receptors in the endosome, receptors recycle to the plasma membrane. Middle panel: Association of LRP with APP mediated by the cytoplasmic scaffolding protein FE65. FE65 can interact via independent PTB domains with the LRP and APP tails. The functional significance of this potential cytoplasmic link for APP processing and/or signaling remains to be shown. Right panel: Dimerization of LRP by α₂M and association with NMDA receptors (NMDAR). Dimerization of LRP on cultured neurons induces NMDA receptor–mediated Ca²⁺ influx. The postsynaptic density protein PSD-95 interacts with LRP and NMDA receptors through different interaction domains. How precisely NMDA receptors are activated by LRP dimerization is not known at present.