Cytoskeleton

Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Peterson, J. R. et al. Nature Struct. Mol. Biol. 4 July 2004 (doi:10.1038/nsmb796)

Using a forward chemical-genetic screen to identify inhibitors of the pathway that mediates the nucleation of actin filaments, the authors identified the small molecule wiskostatin. It binds within a pocket in the GTPase-binding domain (GBD) of neural Wiskott–Aldrich syndrome protein (N-WASP), thereby inducing the GBD to fold into its natural autoinhibited conformation. This interaction is thought to inhibit N-WASP by stabilizing the interaction between the GBD and another domain (the VCA).

Cytoskeleton

Relating microstructure to rheology of a bundled and cross-linked F-actin network in vitro. Shin, J. H. et al. Proc. Natl Acad. Sci. USA 101, 9636–9641 (2004)

Actin-binding proteins (ABPs), which bundle and crosslink actin filaments, are important in regulating the elasticity of the actin cytoskeleton, but techniques to study their effect are lacking. Shin et al. used biochemical techniques, electron microscopy, confocal microscopy and multiparticle tracking to assess the effects of varying the concentration of the ABP scruin. They found that the linear elasticity of the actin–scruin composite network correlated with the properties of individual bundles and their structural organization.

RNA

Dynamics of single mRNPs in nuclei of living cells. Shav-Tal, Y. et al. Science 304, 1797–1800 (2004)

The authors resolved a long-standing controversy, by showing that nuclear mRNA–protein particles (mRNPs) move by free diffusion rather than by an energy-dependent process. By monitoring real-time mRNA expression in single living cells, Shav-Tal et al. studied the movement of thousands of mRNPs in the nucleus. The mobility was not directed, and no accumulation of mRNPs in subnuclear domains was detected.

Mechanism of disease

Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Schaffar, G. et al. Mol. Cell 15, 95–105 (2004)

This study provides new insights into neurodegenerative disorders, such as Huntington's disease, that are caused by expanded polyglutamine (polyQ) mutant proteins. A polyQ-expanded, soluble form of huntingtin bound to certain transcription factors that contain normal polyQ repeats, thereby inhibiting their function and causing cellular toxicity, independent of insoluble aggregates. The presence of chaperone proteins interfered with the conformational change that rendered the mutant huntingtin protein toxic, and prevented the inactivation of transcription factors.