title: Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6.
abstract: Cdc42 is a small GTPase that is required for cell polarity establishment in eukaryotes as diverse as budding yeast and mammals. Par6 is also implicated in metazoan cell polarity establishment and asymmetric cell divisions. Cdc42.GTP interacts with proteins that contain a conserved sequence called a CRIB motif. Uniquely, Par6 possesses a semi-CRIB motif that is not sufficient for binding to Cdc42. An adjacent PDZ domain is also necessary and is required for biological effects of Par6. Here we report the crystal structure of a complex between Cdc42 and the Par6 GTPase-binding domain. The semi-CRIB motif forms a beta-strand that inserts between the four strands of Cdc42 and the three strands of the PDZ domain to form a continuous eight-stranded sheet. Cdc42 induces a conformational change in Par6, detectable by fluorescence resonance energy transfer spectroscopy. Nuclear magnetic resonance studies indicate that the semi-CRIB motif of Par6 is at least partially structured by the PDZ domain. The structure highlights a novel role for a PDZ domain as a structural scaffold.
authors.affiliation: Center for Cell Signaling and Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Garrard
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Capaldo
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rosen
authors.forename: Ian G
authors.initials: IG
authors.lastname: Macara
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D016764:Cell Polarity; D018360:Crystallography, X-Ray; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D031541:Fluorescence Resonance Energy Transfer; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D046911:Macromolecular Substances; D011506:Proteins; D011993:Recombinant Fusion Proteins; D020764:cdc42 GTP-Binding Protein