title: A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein.
abstract: Neurofibromatosis type 1 (NF1) is a common tumour predisposition syndrome associated with numerous clinical complications. Mutations in the tumour suppressor gene NF1 are responsible for disease pathogenesis. This gene encodes the 320 kDa protein neurofibromin, the only clearly defined function of which is to act as a Ras-specific GTPase-activating protein (RasGAP). Here we report the structural discovery of a novel module in neurofibromin, composed of a Sec14p homologous segment and a previously undetected pleckstrin homology (PH)-like domain of potentially novel function. We show phospholipid binding by this bipartite module and identify residues that are involved in this activity; we also show that the PH-like domain is not sufficient for lipid binding. The unique architecture of the domain interface points to a model of how the PH-like domain may regulate binding of a ligand by the Sec14 module.
authors.affiliation: European Molecular Biology Laboratory, Structural and Computational Biology Programme, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: D'Angelo
authors.forename: Stefan
authors.initials: S
authors.lastname: Welti
authors.forename: Fabien
authors.initials: F
authors.lastname: Bonneau
authors.forename: Klaus
authors.initials: K
authors.lastname: Scheffzek
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016147:Genes, Tumor Suppressor; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D025542:Neurofibromin 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D025542:Neurofibromin 1; D010743:Phospholipids