Recombinant Human ASGR1/ASGPR1 Protein, CF

The human asialoglycoprotein receptor (ASGPR) is an endocytic recycling receptor that belongs to the long-form subfamily of the C-type/Ca⁺²-dependent lectin family (1, 2, 3). It is a complex of two noncovalently-linked subunits, a major 46 kDa glycoprotein (ASGR1) and a minor 50 kDa glycoprotein (ASGR2). The major human ASGPR subunit, ASGR1 (also H1), is synthesized as a 291 amino acid (aa) type II transmembrane (TM) glycoprotein. It contains a 40 aa cytoplasmic region, a 21 aa TM segment, and a 230 aa extracellular domain (ECD) (4 - 6). The cytoplasmic region contains one palmitoylation site at Cys36 that is essential for ligand endocytosis and dissociation (7). The ECD contains two important structural regions. The first is a stalk region of 62 aa (aa 61 - 123) that contributes to noncovalent oligomerization. The second is a 118 aa, carbohydrate-binding, Ca⁺²-dependent C-type lectin domain (aa 161 - 278) that is stabilized by three Ca⁺² ions (3, 8). Human ASGR1 ECD is 79% aa identical to mouse ASGR1 ECD. There are two minor (ASGR2) subunits that interact with ASGR1/H1 in a mutually exclusive manner to generate a functional ASGPR (9). They represent alternate splice forms of a type II TM protein. Termed H2b and H2c, H2b differs from H2c only by the presence of a 19 aa insert in its cytoplasmic region. This insert is significant because it allows serine phosphorylation of the cytoplasmic tail and provides for the majority of ASGPR ligand internalization (9). The stoichiometry of a functional ASGPR is unclear, but is suggested to be either a 2:2, 3:1 or 3:2 ratio of ASGR1/H1:ASGR2/H2 (9, 10, 11). ASGPR is found on hepatocytes and a subset of T cells (6, 12). ASGPR is reported to bind Gal (nonreducing), GalNAc, and sialic acid alpha 2,6Gal and GalNAc (3, 13, 14, 15). This is generally within the context of triantennary or tetraantennary configurations (2). The sialic acid terminations are of particular interest because molecules with these motifs most likely represent the endogenous ligands for ASGPR (14).