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 α1LG4-5 domains and provide a mutational analysis of heparin, α-dystroglycan, and galactosyl-sulfatide binding. The two domains of α1LG4-5 are arranged in a V-shaped fashion similar to that observed with laminin α2 LG4-5 but with a substantially different interdomain angle. Recombinant α1LG4-5 binding to heparin, α-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, ²⁷¹⁹RKR and ²⁷⁹¹KRK. Binding to α-dystroglycan was particularly dependent on basic residues within ²⁷¹⁹RKR, ²⁸³¹RAR, and ²⁸⁵⁸KDR. Binding to galactosyl-sulfatide was most affected by mutations in ²⁸³¹RAR and ²⁷⁶⁶KGRTK but not in ²⁷¹⁹RKR. The combined analysis of structure and activities reveal differences in LG domain interactions that should enable dissection of biological roles of different laminin ligands.