The practice of origami dates from the 1600s, but this cannot compare to how long proteins have been evolving form and function. How proteins achieve their correct shape is the subject of this special Focus.
Volume 16 Issue 6, June 2009
News & Views
Removal of the poly(A) tail is the initial step in targeting an mRNA for degradation in budding yeast as well as in metazoans. But in fission yeast a new study reveals an additional pathway that adds uridines to the poly(A) tail of mRNA to initiate the degradation pathway.
Turnover of mRNA has mainly been studied in the budding yeast, Saccharomyces cerevisiae, and is thought to be initiated by deadenylation. Now Rissland and Norbury reveal that additional, parallel decay pathways are at work in the fission yeast, Schizosaccharomyces pombe. They find that mRNA decapping is frequently independent of deadenylation and that Cid1-dependent uridylation of polyadenylated mRNAs seems to stimulate decapping as part of a novel mRNA turnover pathway. As human cells contain Cid1 orthologs, uridylation may form the basis of a widespread, conserved mechanism of mRNA decay.
PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity
Protein kinase C epsilon (PKCε) priming involves phosphorylation of the kinase domain at 3 different sites. Whether these phosphorylation events were autocatalytic was unclear. Now Parker and colleagues use different PKCε mutants and inhibitors to demonstrate that the occupancy of the nucleotide binding pocket, and not catalytic activity, promote priming of PKCε.
The amino-terminal domain (ATD) of ionotropic glutamate receptors (iGluRs) mediates their assembly into AMPA-, kainate- and NMDA-sensitive subtypes. The crystal structure of the ATD from the kainate receptor GluR6 reveals a dimeric organization and likely determinants for subtype-selective assembly.
Loss of the Mili-interacting Tudor domain–containing protein-1 activates transposons and alters the Mili-associated small RNA profile
piRNAs have been implicated in transposon silencing. Tudor domain–containing protein-1 (Tdrd1) is now shown to interact with the mouse Piwi ortholog Mili and be part of a complex that contains Mili-associated piRNAs. Interaction occurs through the N terminus of Mili, which is dimethylated, a modification that promotes Tdrd1 interaction. The Tdrd1 mutant shares phenotypes with the Mili mutant but shows a strong effect on the nature of the small RNA pool associated with Mili.
Bacterial ubiquitin-like modifier Pup is deamidated and conjugated to substrates by distinct but homologous enzymes
Pupylation is the bacterial equivalent of ubiquitin conjugation, and it involves C-terminal Pup conjugation to lysines to target proteins for proteasomal degradation. This modification reaction has now been reconstituted in vitro using enzymes from the pathogen Mycobacterium tuberculosis. The Pup deamidase (Dop) of this pathway has been defined, and PafA has been shown to conjugate deamidated Pup to substrates.
Sertraline (Zoloft) and fluoxetine (Prozac) are selective serotonin-reuptake inhibitors (SSRIs) that are widely prescribed to treat depression. They bind to the presynaptic plasma membrane serotonin transporter (SERT) and inhibit serotonin uptake. Both these drugs possess halogen atoms, but the structural basis for the specificity of SERT for these inhibitors was not known. Zhou et al. now report the crystal structure of LeuT, a bacterial SERT homolog in complex with three different SSRIs. The halogen atoms of all three bind within exactly the same pocket of LeuT, and mutations within this pocket in SERT markedly reduce the transporter's affinity for SSRIs but not for tricyclic antidepressants.
The signaling adaptor TRAF6 is a ubiquitin E3 ligase whose activity can lead to activation of NF-κB and MAPK pathways. New data based on the structure of TRAF6 in complex with the ubiquitin E2 Ubc13 suggest that other TRAFs do not interact with Ubc13 and that oligomerization of TRAF6 is needed for downstream signal transduction.
Topoisomerases alter DNA topology, an essential activity in all organisms. Bacterial type II topoisomerases are targets for antimicrobials such as quinolones, whose binding mode was unclear. Now the crystal structures of pneumococcal topoisomerase IV in a DNA cleavage complex bound to moxifloxacin or clinafloxacin provide insight into how these drugs work and how bacteria can acquire resistance.
A large-scale screen for changes in alternative splice forms in cancer now reveals that almost half of the active alternative splicing events are shifted in breast and ovarian cancer tissues. In addition, many of these changes occur near consensus binding sequences for FOX2 binding sites. This correlates with changes in Fox2 expression or splicing in tissues assessed, and FOX2 depletion results in similar shifts in splice isoforms.
To be functional, most proteins need to reach their correct three-dimensional structure, through a process called folding. Defects in protein folding can lead to protein aggregation or degradation and are associated with several pathological conditions. To bring readers up to date on the basic concepts and the latest developments in the field, Nature Structural & Molecular Biologypresents a focus issue on 'Protein Folding', with four commissioned Reviews and two Perspectives.