Volume 16 Issue 3, March 2009

The influenza virus has proved an elusive target in the development of broadly protective vaccines. A new study identifies an antibody with broad neutralizing activity against influenza viruses of different subtypes. The antibody recognizes a highly conserved region on the viral hemagglutinin that may be targeted to prevent infection.

Intermediate conformations of the Hsp90 ATPase cycle have been identified in solution by fluorescence resonance energy transfer, and the impact of nucleotides and of modulatory cochaperones has been visualized in real time.

KSRP is involved in mRNA instability, a role that is repressed upon AKT kinase–mediated phosphorylation, which promotes 14-3-3 interaction. This modification site is now shown to be exposed upon AKT phosphorylation through unfolding of the KH1 domain of KSRP, an event that allows 14-3-3 interaction, which in turn affects nuclear cytoplasmic partitioning.

The DEAD-box protein DBP5 is involved in yeast mRNA export, though the mechanism by which it helps to remodel and release transcripts on the cytoplasmic face of the nuclear pore complex has been unclear. The structures of DBP5 in complex with the mRNA and AMPPNP, as well as with the nucleoporin NUP214, indicate that the transcript and nucleoporin compete for the same binding site, suggesting a model for the sequence of events occurring at the last step of export.

Meiosis is a highly conserved and tightly regulated process in which one round of DNA synthesis is followed by two rounds of division. By studying the expression of crs1 pre-mRNA, a meiotic cyclin in fission yeast, Wise and co-workers found that increased RNA accumulation during meiosis is not due to an increase in transcription but rather is a result of RNA processing and turnover. Moreover, they found that polyadenylation of crs1 is linked to splicing, a coupling previously thought to occur only in mammals. They suggest that this highly integrated crs1 regulatory system may allow a rapid response to adverse conditions.

A group of neutralizing monoclonal antibodies (mAbs) targeting the influenza A hemagglutinin has been selected and characterized. Remarkably, these mAbs were able to neutralize a broad array of group 1 strains and could protect mice from infection when given prophylactically or therapeutically. The crystal structure of one such mAb in complex with hemagglutinin provides insight into its mechanism of neutralization and broad specificity.

Rare codons along transcripts have been proposed to influence the local rate of translation and the folding of nascent polypeptide chains. Now this idea is demonstrated for a bacterial protein: rare-codon clusters are shown to affect translation rates, and this was important for efficient protein folding in vitro and in vivo.

The Hsp90 chaperone is responsible for the stabilization of a large variety of regulatory proteins. Single-molecule FRET was used to examine the conformational dynamics of Hsp90 in its different nucleotide-bound states. The findings suggest that, in the absence of substrate and cochaperone proteins, Hsp90's conformational changes are not strongly coupled to ATP hydrolysis.

The Hsp90 chaperone is responsible for the stabilization of a large variety of regulatory proteins. By labeling the subunits in the Hsp90 homodimer with different dyes and in different positions, the kinetics of Hsp90 conformational changes along the ATPase cycle was characterized, revealing different intermediate states and the different roles of cochaperones.

Mek1 and Mek2 are kinases that phosphorylate Erk, participating in the signal transduction pathway controlling cellular growth and adhesion. Though closely related, there are clear functional differences, with Mek1 being subject to negative-feedback regulation via phosphorylation by Erk. Now Mek1 and Mek2 are shown to form a heterodimer in vivo, in which Mek2 activity is also controlled by Erk phosphorylation of Mek1.

Mammalian gene silencing is associated with both histone and DNA methylation. The PRMT5 arginine histone methyltransferase is now found to affect DNA methylation at the γ-globin locus in mice. This is mediated by an effect on recruitment of the DNA methyltransferase DNMT3A, but through interaction with the product of PRMT5 activity. This suggests that DNMT3A reads the histone methylation, coupling it to nearby DNA methylation.

The G9a-like lysine methyltransferases can be inhibited by the small molecule BIX-01294, recently identified through a chemical screen and shown to be capable of replacing Oct3/4. The structure of GLP in complex with BIX-01294 indicates an overlap with the known position of histone peptide binding, and further work indicates that the drug inhibits methylation of DNMT1, indicating that it is enzyme specific but non specific with regard to substrate.

Im7 is a small Escherichia coli colicin binding protein that uses a remarkably complex folding pathway. Analysis of the Im7 folding landscape reveals details of the earliest transition state in its folding pathway and indicates that the formation of non-native contacts that result in intermediate folding states is necessary to maintain elements essential to the protein's function.

The ATPase and the microtubule binding domains of dynein are separated by a long stalk coiled coil, which has to communicate and coordinate the activities of these domains along the mechanochemical cycle. Now this communication is shown to occur via sliding of the α-helices of the coiled coil.

Photosystem II (PSII) catalyzes the first light-dependent step in photosynthesis. An improved structural model of a cyanobacterial PSII provides complete assignment of all subunits in the complex and reveals possible channels used for the transport of protons, oxygen and water to the thylakoid lumen.

Riboswitches are RNA domains that alter gene expression in response to ligand binding. The structure of the Bacillus subtilis preQ1 ribsoswitch, which recognizes the conserved modified nucleobase preQ1, in complex with its ligand indicates how an RNA of only 34 nucleotides recognizes its ligand.