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Nat Commun. 2016 Mar 3;7:10827. doi: 10.1038/ncomms10827.

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

Author information

1
School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
2
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
3
Nanoscale Physics Research Laboratory, School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT, UK.
4
School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK.
5
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.

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.

PMID:
26935805
PMCID:
PMC4782060
DOI:
10.1038/ncomms10827
[Indexed for MEDLINE]
Free PMC Article

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