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Mechanism of intermediate filament recognition by plakin repeat domains revealed by envoplakin targeting of vimentin

Author

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  • Claudia Fogl

    (School of Cancer Sciences, University of Birmingham)

  • Fiyaz Mohammed

    (Institute of Immunology and Immunotherapy, University of Birmingham)

  • Caezar Al-Jassar

    (School of Cancer Sciences, University of Birmingham
    Present address: MRC-LMB, University of Cambridge, Cambridge CB2 0QH, UK (C.A.-J.); Department of Biochemistry, Faculty of Medicine and Dentistry, 474 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 (M.O.))

  • Mark Jeeves

    (School of Cancer Sciences, University of Birmingham)

  • Timothy J. Knowles

    (School of Cancer Sciences, University of Birmingham)

  • Penelope Rodriguez-Zamora

    (Nanoscale Physics Research Laboratory, School of Physics and Astronomy, University of Birmingham)

  • Scott A. White

    (School of Biosciences, University of Birmingham)

  • Elena Odintsova

    (Institute of Cancer and Genomic Sciences, University of Birmingham)

  • Michael Overduin

    (School of Cancer Sciences, University of Birmingham
    Present address: MRC-LMB, University of Cambridge, Cambridge CB2 0QH, UK (C.A.-J.); Department of Biochemistry, Faculty of Medicine and Dentistry, 474 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 (M.O.))

  • Martyn Chidgey

    (School of Cancer Sciences, University of Birmingham)

Abstract

Plakin proteins form critical connections between cell junctions and the cytoskeleton; their disruption within epithelial and cardiac muscle cells cause skin-blistering diseases and cardiomyopathies. Envoplakin has a single plakin repeat domain (PRD) which recognizes intermediate filaments through an unresolved mechanism. Herein we report the crystal structure of envoplakin’s complete PRD fold, revealing binding determinants within its electropositive binding groove. Four of its five internal repeats recognize negatively charged patches within vimentin via five basic determinants that are identified by nuclear magnetic resonance spectroscopy. Mutations of the Lys1901 or Arg1914 binding determinants delocalize heterodimeric envoplakin from intracellular vimentin and keratin filaments in cultured cells. Recognition of vimentin is abolished when its residues Asp112 or Asp119 are mutated. The latter slot intermediate filament rods into basic PRD domain grooves through electrosteric complementarity in a widely applicable mechanism. Together this reveals how plakin family members form dynamic linkages with cytoskeletal frameworks.

Suggested Citation

  • Claudia Fogl & Fiyaz Mohammed & Caezar Al-Jassar & Mark Jeeves & Timothy J. Knowles & Penelope Rodriguez-Zamora & Scott A. White & Elena Odintsova & Michael Overduin & Martyn Chidgey, 2016. "Mechanism of intermediate filament recognition by plakin repeat domains revealed by envoplakin targeting of vimentin," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10827
    DOI: 10.1038/ncomms10827
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