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 secreted 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 structure at 3.1 A resolution of the FS-EC domain pair of human BM-40. The two distinct domains interact through a small interface that involves the EF-hand pair of the EC domain. Residues implicated in cell binding, inhibition of cell spreading and disassembly of focal adhesions cluster on one face of BM-40, opposite the binding epitope for collagens and the N-linked carbohydrate. The elongated FS domain is structurally related to serine protease inhibitors of the Kazal family. Notable 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 spacer in proteins containing tandemly repeated FS domains, such as follistatin and agrin, and forms the heparin-binding site in follistatin.
Hohenester
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Department of Crystallography, Birkbeck College, London, UK.
Maurer
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Timpl
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R
D018171:Agrin / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004815:Epidermal Growth Factor / Q000737:chemistry; D005164:Factor IX / Q000737:chemistry; D038681:Follistatin; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015676:Osteonectin / Q000737:chemistry* / Q000378:metabolism; D010059:Ovomucin / Q000737:chemistry; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000737:chemistry
D018171:Agrin; D038681:Follistatin; D006023:Glycoproteins; D015676:Osteonectin; D010059:Ovomucin; D014359:Trypsin Inhibitor, Kazal Pancreatic; D004815:Epidermal Growth Factor; D005164:Factor IX; D002118:Calcium