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The structure of FMNL2–Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation

Author

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  • Sonja Kühn

    (Center of Advanced European Studies and Research, Group Physical Biochemistry
    Max Planck Institute of Molecular Physiology)

  • Constanze Erdmann

    (Center of Advanced European Studies and Research, Group Physical Biochemistry
    Max Planck Institute of Molecular Physiology)

  • Frieda Kage

    (Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn
    Zoological Institute, Technical University Braunschweig)

  • Jennifer Block

    (Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn)

  • Lisa Schwenkmezger

    (Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn)

  • Anika Steffen

    (Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn
    Helmholtz Centre for Infection Research)

  • Klemens Rottner

    (Institute of Genetics, Actin Dynamics and Motility Unit, University of Bonn
    Zoological Institute, Technical University Braunschweig
    Helmholtz Centre for Infection Research)

  • Matthias Geyer

    (Center of Advanced European Studies and Research, Group Physical Biochemistry
    Max Planck Institute of Molecular Physiology
    Institute of Innate Immunity)

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.

Suggested Citation

  • Sonja Kühn & Constanze Erdmann & Frieda Kage & Jennifer Block & Lisa Schwenkmezger & Anika Steffen & Klemens Rottner & Matthias Geyer, 2015. "The structure of FMNL2–Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8088
    DOI: 10.1038/ncomms8088
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    1. Fabienne Kocher & Violetta Applegate & Jens Reiners & Astrid Port & Dominik Spona & Sebastian Hänsch & Amin Mirzaiebadizi & Mohammad Reza Ahmadian & Sander H. J. Smits & Johannes H. Hegemann & Katja M, 2024. "The Chlamydia pneumoniae effector SemD exploits its host’s endocytic machinery by structural and functional mimicry," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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