In the PNAS Early Edition this week, researchers describe their discovery that amyloidogenic light chain (AL-LC) proteins induce oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyoctes through the activation of p38α mitogen-activated protein kinase. The team found the AL-LC-induced p38 activation to be independents of the upstream MAPK kinase, MKK3/6. “Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB-1-mediated p38α MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure,” the team writes.
A team of researchers from the University of California, Los Angeles, report on their simulation study that confers with the notion that enzymes work by electrostatic preorganization. The team writes that their research provides further support for investigation of the origin of enzyme catalysis using the ketosteroid isomerase reaction, and that a well-defined physical concept is crucial in order to examine catalytic effects.
Researchers from Sweden and Switzerland describe their quantitative study of synthetic Hox transcription factor-DNA interactions in live cells. Their paper, in this week’s PNAS Early Edition, presents a “controllable system for quantitative studies of protein-DNA interactions in live cells that enables us to ‘titrate’ the concentration of the synthetic [Sex combs reduced] Scr peptides in a single cell,” the team writes. Using methods with single-molecule sensitivity, fluorescence imaging, and fluorescence correlations spectroscopy, the team was able to investigate the kinetics of Scr-DNA interactions in vivo.
In a commentary published online ahead of print, Robert Craigie, of the National Institute of Diabetes and Digestive and Kidney Diseases, discusses targeting HIV-1 DNA integration by swapping lens epithelium-derived growth factor (LEDGF) tethers. He suggests that a paper in the same issue of PNAS, by Andrea L. Ferris, of the National Cancer Institute, et al. provides “potential importance in the application of retroviral vectors for gene therapy,” having demonstrated that the half of LEDGF that binds chromatin can be swapped to practically any chromatin binding domain. “Although the extent to which retroviral target specificity can be directed remains to be determined, manipulating the dual-anchor LEDGF, which bridges the [preintegration complex] PIC and chromatin before integration, is the most promising strategy to date,” Craigie writes.