Modeling the three-dimensional structure of serpin molecular chaperone HSP47

Heat shock protein 47 (HSP47) is a molecular chaperone which assists procollagen triple helix assembly and secretion. As a molecular chaperone it is unique in that it binds specifically to a very narrow range of protein ''substrates'' (i.e., procollagen and collagen only), and it is also a member of the well-characterized serine protease inhibitor (serpin) superfamily. In the absence; of any X-ray crystallographic data, a novel tandem-modeling procedure is used to obtain three-dimensional structural information on mature recombinant mouse HSP47 (mrmHSP47). MrmHSP47 is shown to have 30% amino acid sequence identity and 70% sequence similarity with human protein C inhibitor (hPCI). Therefore, molecular models of inhibitory and latent states of hPCI are generated, using the X-ray crystal structure coordinates of proteolytically cleaved hPCI, and used as templates for the homology modeling of inhibitory and latent states of mrmHSP47. The validity of the models is discussed and the latent state model of mrmHSP47 is shown to have a suitable candidate binding groove for procollagen/collagen peptides, which appears to account for experimental observations made with aminoacid deletion experiments. (C) 1995 Academic Press, Inc.