CRYSTAL-STRUCTURE OF A PAIR OF FOLLISTATIN-LIKE AND EF-HAND CALCIUM-BINDING DOMAINS IN BM-40

BM-40 (also known as SPARC or osteonectin) is an anti-adhesive secrete d glycoprotein involved in tissue remodelling. Apart from an acidic N- terminal segment, BM-40 consists of a follistatin-like (FS) domain and an EF-hand calcium-binding (EC) domain. Here we report the crystal st ructure at 3.1 Angstrom resolution of the FS-EC domain pair of human B M-40, The two distinct domains interact through a small interface that involves the EF-hand pair of the EC domain. Residues implicated in ce ll binding, inhibition of cell spreading and disassembly of focal adhe sions cluster on one face of BM-40, opposite the binding epitope for c ollagens and the N-linked carbohydrate. The elongated FS domain is str ucturally related to serine protease inhibitors of the Kazal family. N otable differences are an insertion into the inhibitory loop in BM-40 and a protruding N-terminal beta-hairpin with striking similarities to epidermal growth factor. This hairpin is likely to act as a rigid spa cer in proteins containing tandemly repeated FS domains, such as folli statin and agrin, and forms the heparin-binding site in follistatin.