2022
DOI: 10.1038/s41598-022-25732-y
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Molecular basis of C9orf72 poly-PR interference with the β-karyopherin family of nuclear transport receptors

Abstract: Nucleocytoplasmic transport (NCT) is affected in several neurodegenerative diseases including C9orf72-ALS. It has recently been found that arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72 repeat expansions, directly bind to several importins. To gain insight into how this can affect nucleocytoplasmic transport, we use coarse-grained molecular dynamics simulations to study the molecular interaction of poly-PR, the most toxic DPR, with several Kapβs (importins and exportins). We sh… Show more

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Cited by 24 publications
(48 citation statements)
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References 69 publications
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“…Coarse-grained molecular dynamics simulations were performed with the implicit-solvent 1BPA-1.1 model for intrinsically disordered proteins (Ghavami et al, 2013, 2014; Jafarinia et al, 2020, 2022; Dekker et al, 2022). This residue-scale model discriminates between all 20 amino acids through residue-specific hydrophobic, charge and cation–pi interactions, and accounts for the sequence-specific backbone stiffness (see Dekker et al (2022) for a detailed description of the 1BPA-1.1 model).…”
Section: Methodsmentioning
confidence: 99%
See 1 more Smart Citation
“…Coarse-grained molecular dynamics simulations were performed with the implicit-solvent 1BPA-1.1 model for intrinsically disordered proteins (Ghavami et al, 2013, 2014; Jafarinia et al, 2020, 2022; Dekker et al, 2022). This residue-scale model discriminates between all 20 amino acids through residue-specific hydrophobic, charge and cation–pi interactions, and accounts for the sequence-specific backbone stiffness (see Dekker et al (2022) for a detailed description of the 1BPA-1.1 model).…”
Section: Methodsmentioning
confidence: 99%
“…Coarse-grained molecular dynamics simulations were performed with the implicit-solvent 1BPA-1.1 model for intrinsically disordered proteins (Ghavami et al, 2013(Ghavami et al, , 2014Jafarinia et al, 2020Jafarinia et al, , 2022Dekker et al, 2022). This residue-scale model discriminates between all 20 amino acids through residue-specific hydrophobic, charge and cation-pi interactions, were generated from partly-overlapping sterically inert beads with a diameter of 3.0 nm with their centres placed 1.5 nm apart.…”
Section: Coarse-grained Molecular Dynamics Simulationsmentioning
confidence: 99%
“…For expression of Nsp1FG domain in E. coli the intron in the starting codon was absent 39 . To assess the effect of Nsp1FG-domain on other FG-domains, purified proteins were diluted in the assay buffer (50 mM Tris-HCl and 150 mM NaCl, pH Coarse-grained molecular dynamics simulations Simulations were performed with the coarse-grained 1BPA-1.1 model for IDPs [77][78][79]110,111 .…”
Section: Protein Purification and Llps And Aggregation Assaysmentioning
confidence: 99%
“…Genes involving nucleocytoplasmic transportation were identified from yeast ( 22 ) or Drosophila ( 21 ) screening which can modify poly-GR/poly-PR toxicity. Poly-PR was also found to directly binding to nuclear pores of Xenopus laevis oocyte ( 23 ) and β-karyopherin family ( 24 ). Beside proteins, RNA transportation is also compromised in Drosophila -expressed G 4 C 2 expansions ( 21 ).…”
Section: Discussionmentioning
confidence: 99%
“…We further investigated if nucleocytoplasmic transportation was compromised by the treatment of poly-GR/PR peptides which was assayed in many groups (10)(11)(12)(13)(21)(22)(23)(24). We constructed a reporter plasmid containing double EGFP conjugated with a nuclear export sequence (NES) and a nuclear localization sequence (NLS) (fig.…”
Section: Poly-gr/pr Blocks Nucleocytoplasmic Transport At Later Stagementioning
confidence: 99%