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Hundt N, Preller M, Swolski O, Marryza A, Mannherz HG, Manstein DJ, Müller M (2014)


Molecular mechanisms of disease-related human β-actin mutations p.R183W and p.E364K.

FEBS J., doi:10.1111/febs.13068.





Cytoplasmic β-actin supports fundamental cellular processes in healthy and diseased cells including cell adhesion, migration, cytokinesis, and maintenance of cell polarity. Mutations in ACTB, the gene encoding cytoplasmic β-actin, lead to severe disorders with a broad range of symptoms. The two dominant heterozygous gain-of-function β-actin mutations p.R183W and p.E364K were identified in patients suffering from developmental malformations, deafness and juvenile-onset dystonia (p.R183W) and neutrophil dysfunction (p.E364K). Here, we report the recombinant production and functional characterization of the two mutant proteins. Arginine-183 is located near the nucleotide-binding pocket of actin. Our results from biochemical studies and molecular dynamics simulations show that replacement by a tryptophan residue at position 183 establishes an unusual stacking interaction with Y69 that perturbs nucleotide release from actin monomers and polymerization behavior by inducing a closed state conformation. The replacement of glutamate-364 by a lysine residue appears to act as an allosteric trigger event leading to the preferred formation of the closed state. Thus, our approach indicates that both mutations affect inter-domain mobility and nucleotide interactions as a basis for the formation of disease phenotypes in patients.