MOLECULAR MODELING OF THE NORRIE DISEASE PROTEIN PREDICTS A CYSTINE KNOT GROWTH-FACTOR TERTIARY STRUCTURE

The X-lined gene for Norrie disease, which is characterized by blindne ss, deafness and mental retardation has been cloned recently. This gen e has been thought to code for a putative extracellular factor; its pr edicted amino acid sequence is homologous to the C-terminal domain of diverse extracellular proteins. Sequence pattern searches and three-di mensional modelling now suggest that the Norrie disease protein (NDP) has a tertiary structure similar to that of transforming growth factor beta (TGF beta). Our model identifies NDP as a member of an emerging family of growth factors containing a cystine knot motif, with direct implications for the physiological role of NDP. The model also sheds l ight on sequence related domains such as the C-terminal domain of muci ns and of von Willebrand factor.