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The hyaluronan (HA) receptor for endocytosis (HARE) is a multifunctional recycling clearance receptor for 14 different ligands, including HA and heparin (Hep), which bind to discrete nonoverlapping sites. Four different functional endocytic motifs ( M ) in the cytoplasmic domain (CD) target coated pit mediated uptake: (YSYFRI 2485  ( M1 ), FQHF 2495  ( M2 ), NPLY 2519  ( M3 ), and DPF 2534  ( M4 )). We previously found (Pandey et al. J. Biol. Chem. 283, 21453, 2008) that  M1 ,  M2 , and  M3  mediate endocytosis of HA. Here we assessed the ability of HARE variants with a single-motif deletion or containing only a single motif to endocytose HA or Hep. Single-motif deletion variants lacking  M1, M3 , or  M4  (a different subset than involved in HA uptake) showed decreased Hep endocytosis, although  M3  was the most active; the remaining redundant motifs did not compensate for loss of other motifs. Surprisingly, a HARE CD variant with only  M3  internalized both HA and Hep, whereas variants with either  M2  or  M4  alone did not endocytose either ligand.  Internalization of HA and Hep by HARE CD mutants was dynamin-dependent and was inhibited by hyperosmolarity, confirming clathrin-mediated endocytosis. The results indicate a complicated relationship among multiple CD motifs that target coated pit uptake and a more fundamental role for motif  M3 .

HARE-Mediated Endocytosis of Hyaluronan and Heparin Is Targeted by Different Subsets of Three Endocytic Motifs