Crystal structure and cell surface anchorage sites of laminin α1LG4-5

The laminin G-like ( LG) domains of laminin-111, a glycoprotein widely expressed during embryogenesis, provide cell anchoring and receptor binding sites that are involved in basement membrane assembly and cell signaling. We now report the crystal structure of the laminin alpha 1LG4-5 domains and provide a mutational analysis of heparin, alpha-dystroglycan, and galactosyl-sulfatide binding. The two domains of alpha 1LG4-5 are arranged in a V-shaped fashion similar to that observed with laminin alpha 2 LG4-5 but with a substantially different interdomain angle. Recombinant alpha 1LG4-5 binding to heparin, alpha-dystroglycan, and sulfatides was dependent upon both shared and unique contributions from basic residues distributed in several clusters on the surface of LG4. For heparin, the greatest contribution was detected from two clusters, (RKR)-R-2719 and (KRK)-K-2791. Binding to alpha-dystroglycan was particularly dependent on basic residues within (RKR)-R-2719, (2831)RAR, and (KDR)-K-2858. Binding to galactosyl-sulfatide was most affected by mutations in (2831)RAR and (2766)KGRTK but not in (RKR)-R-2719. The combined analysis of structure and activities reveal differences in LG domain interactions that should enable dissection of biological roles of different laminin ligands.