Model for the three-dimensional structure of vitronectin: Predictions for the multi-domain protein from threading and docking

The structure of vitronectin, an adhesive protein that circulates in high c oncentrations in human plasma, was predicted through a combination of compu tational methods and experimental approaches. Fold recognition and sequence -structure alignment were performed using the threading program PROSPECT fo r each of three structural domains, i.e., the N-terminal somatomedin B doma in (residues 1-53), the central region that folds into a four-bladed beta - propeller domain (residues 131-342), and the C-terminal heparin-binding dom ain (residues 347-459). The atomic structure of each domain was generated u sing MODELLER, based on the alignment obtained from threading. Docking expe riments between the central and C-terminal domains were conducted using the program GRAM, with limits on the degrees of freedom from a known inter-dom ain disulfide bridge. The docked structure has a large inter-domain contact surface and defines a putative heparin-binding groove at the inter-domain interface. We also docked heparin together with the combined structure of t he central and C-terminal domains, using GRAMM. The predictions from the th reading and docking experiments are consistent with experimental data on pu rified plasma vitronectin pertaining to protease sensitivity, ligand-bindin g sites, and buried cysteines. (C) 2001 Wiley-Liss, Inc.