title: The structure of FMNL2-Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation.
abstract: Formins are actin polymerization factors that elongate unbranched actin filaments at the barbed end. Rho family GTPases activate Diaphanous-related formins through the relief of an autoregulatory interaction. The crystal structures of the N-terminal domains of human FMNL1 and FMNL2 in complex with active Cdc42 show that Cdc42 mediates contacts with all five armadillo repeats of the formin with specific interactions formed by the Rho-GTPase insert helix. Mutation of three residues within Rac1 results in a gain-of-function mutation for FMNL2 binding and reconstitution of the Cdc42 phenotype in vivo. Dimerization of FMNL1 through a parallel coiled coil segment leads to formation of an umbrella-shaped structure that—together with Cdc42—spans more than 15 nm in diameter. The two interacting FMNL-Cdc42 heterodimers expose six membrane interaction motifs on a convex protein surface, the assembly of which may facilitate actin filament elongation at the leading edge of lamellipodia and filopodia.
authors.affiliation: 1] Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, Bonn 53175, Germany [2] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund 44227, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kühn
authors.affiliation: 1] Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, Bonn 53175, Germany [2] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund 44227, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Erdmann
authors.affiliation: 1] Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn, Karlrobert-Kreiten-Strasse 13, Bonn 53115, Germany [2] Division of Molecular Cell Biology, Zoological Institute, Technical University Braunschweig, Spielmannstrasse 7, Braunschweig 38106, Germany.
authors.forename: Frieda
authors.initials: F
authors.lastname: Kage
authors.affiliation: Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn, Karlrobert-Kreiten-Strasse 13, Bonn 53115, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Block
authors.affiliation: Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn, Karlrobert-Kreiten-Strasse 13, Bonn 53115, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schwenkmezger
authors.affiliation: 1] Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn, Karlrobert-Kreiten-Strasse 13, Bonn 53115, Germany [2] Helmholtz Centre for Infection Research, Department of Cell Biology, Inhoffenstrasse 7, Braunschweig 38124, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Steffen
authors.affiliation: 1] Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn, Karlrobert-Kreiten-Strasse 13, Bonn 53115, Germany [2] Division of Molecular Cell Biology, Zoological Institute, Technical University Braunschweig, Spielmannstrasse 7, Braunschweig 38106, Germany [3] Helmholtz Centre for Infection Research, Department of Cell Biology, Inhoffenstrasse 7, Braunschweig 38124, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rottner
authors.affiliation: 1] Center of Advanced European Studies and Research, Group Physical Biochemistry, Ludwig-Erhard-Allee 2, Bonn 53175, Germany [2] Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund 44227, Germany [3] Institute of Innate Immunity, Department of Structural Immunology, Sigmund-Freud-Str. 25, Bonn 53127, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D011232:Chemical Precipitation; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D000080865:Formins; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000502:physiology*; D013816:Thermodynamics; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; C476204:FMNL1 protein, human; C476208:FMNL2 protein, human; D000080865:Formins; D011506:Proteins; D020764:cdc42 GTP-Binding Protein