Phosphorylation of LRP1 regulates the interaction with Fe65

► Fe65 directly interacts with the intracellular domains of LRP1 (LICD) and APP (AICD). ► Fe65/LICD interaction depends on tyrosine phosphorylation in the 2nd NPVY motif. ► Mutations of two Fe65 arginines impair complex formation with phosphorylated LICD. ► Fe65-PTB1 and Fe65-PTB2 are flexibly linked and can interact as independent modules.