Crystal structure of the carbohydrate recognition domain of the H1 subunitof the asialoglycoprotein receptor

The human asialoglycoprotein receptor (ASGPR), also called hepatic lectin, is an integral membrane protein and is responsible for the clearance of des ialylated, galactose-terminal glycoproteins from the circulation by recepto r-mediated endocytosis. It can be subdivided into four functional domains: the cytosolic domain, the transmembrane domain, the stalk and the carbohydr ate recognition domain (CRD). The galactose-binding domains belong to the s uperfamily of C-type (calcium-dependent) lectins, in particular to the long -form subfamily with three conserved intramolecular disulphide bonds. It is able to bind terminal non-reducing galactose residues and N-acetyl-galacto samine residues of desialated tri or tetra-antennary N-linked glycans. The ASGPR is a potential liver-specific receptor for hepatitis B virus and Marb urg virus and has been used to target exogenous molecules specifically to h epatocytes for diagnostic and therapeutic purposes. Here, we present the X-ray crystal structure of the carbohydrate recognitio n domain of the major subunit H1 at 2.3 Angstrom resolution. While the over all fold of this and other known C-type lectin structures are well con serv ed, the positions of the bound calcium ions are not, indicating that the fo ld is stabilised by alternative mechanisms in different branches of the C-t ype lectin family. It is the first CRD structure where three calcium ions f orm an intergral part of the structure. In addition, the structure provides direct confirmation for the conversion of the ligand-binding site of the m annose-binding protein to an asialoglycoprotein receptor-like specificity s uggested by Drickamer and colleagues. In agreement with the prediction that the coiled-coil domain of the ASGPR is separated from the CRD and its N-te rminal disulphide bridge by several residues, these residues are indeed not alpha-helical, while in tetranectin they form an alpha-helical coiled-coil . (C) 2000 Academic Press.