Structure of the C-terminal laminin G-like domain pair of the laminin α2 chain harbouring binding sites for α-dystroglycan and heparin

The laminins are large heterotrimeric glycoproteins with fundamental roles in basement membrane architecture and function. The C‐terminus of the laminin α chain contains a tandem of five laminin G‐like (LG) domains. We report the 2.0 Å crystal structure of the laminin α2 LG4–LG5 domain pair, which harbours binding sites for heparin and the cell surface receptor α‐dystroglycan, and is 41% identical to the laminin α1 E3 fragment. LG4 and LG5 are arranged in a V‐shaped fashion related by a 110° rotation about an axis passing near the domain termini. An extended N‐terminal segment is disulfide bonded to LG5 and stabilizes the domain pair. Two calcium ions, one each in LG4 and LG5, are located 65 Å apart at the tips of the domains opposite the polypeptide termini. An extensive basic surface region between the calcium sites is proposed to bind α‐dystroglycan and heparin. The LG4–LG5 structure was used to construct a model of the laminin LG1–LG5 tandem and interpret missense mutations underlying protein S deficiency.