News & Views in 2007

Last year Zhang, Kuriyan and colleagues demonstrated that an asymmetric dimer interaction between EGF receptor kinase domains is a key element of receptor activation. They now show that a cellular protein that inhibits receptor activity targets this dimer interface, not only uncovering an important regulatory mechanism but also opening a new route to therapeutic kinase inhibition.

Transcription factors 'recognize' relatively short DNA consensus sequences; their full specificity must depend on a broader set of protein-protein and protein-DNA interactions. Joshi et al. show that, in addition to forming base pair–specific hydrogen bonds in the DNA major groove, certain Hox proteins detect DNA shape in the minor groove.

The demonstrated ability of modern DNA-dependent RNA polymerases to use RNA templates for productive RNA synthesis suggests that they evolved from ancient RNA-dependent RNA replicases.

Faced with the thermodynamic and kinetic challenge of finding a few specific sites on DNA among millions of nonspecific sites, within a limited amount of time, what's a protein to do? Single-molecule studies show that some proteins have selected sliding on DNA as a solution.

Post-translational modification of histones can profoundly affect chromatin structure and function. The discovery that histone H3 Arg2 methylation is a widespread silencing modification that inhibits histone H3 Lys4 trimethylation extends our understanding of how active and silenced chromatin states are maintained.

Two new studies point to a heretofore underappreciated mechanism by which chromatin higher-order structure can be regulated by surfaces in the nucleosome that are not associated with DNA.

Proline isomerization of the p53 transactivation domain has a central role in coordinating kinase signaling pathways that assemble the core p53 transcription complex.

Through its crucial role in DNA damage recognition and initiation of nucleotide excision repair in mammals, XPC protein represents a first line of defense against carcinogenesis. The recent elucidation of the molecular structure of the yeast XPC homolog Rad4 provides new insights into how eukaryotic cells recognize structurally diverse DNA lesions.

The high stability of SNARE complexes is probably crucial for their role in membrane fusion, but it has been difficult to measure. A surface-forces apparatus has now been used to measure the stabilization energy of a partially assembled SNARE complex, and the result (35 k_BT) is among the highest protein-folding free energies ever observed. Moreover, this approach offers a bright future for further structural and energetic studies of membrane fusion machineries.

Prion 'strains', multiple conformations of the same misfolded protein, have captured great interest because of their role in transmission of mad cow disease to humans. Prion strains have also been observed in yeast, where self-propagating protein folds are responsible for inheritable traits. Recent findings reveal an exciting new insight into the structural basis of this phenomenon.

A recent study using electron microscopy provides a detailed view of the oligomerization of a protein complex on the surface of a microtubule polymer. The findings point to a new type of interaction that may be well suited to couple the movement of cargo to dynamic cytoskeletal polymers.

Using a previously developed method, Singer and co-workers have now labeled RNA transcripts and quantitatively measured the synthesis of RNA in living cells. They find that only a small fraction of the RNA polymerases that bind the promoter actually produce messenger RNA. They also observed much faster elongation than previously reported, along with frequent long pauses.

Neurotransmitter:sodium symporters, which use sodium gradients for the coupled uptake of sodium and neurotransmitters during synaptic transmission, often display a chloride dependence. New data from two separate groups identify the chloride-binding site for this family of symporters and suggest that the chloride charge facilitates sodium binding and substrate transport.

Targeting of enzymes regulating chromatin organization to specific histone residues is a key element in the hugely complex system of epigenetic signaling that controls gene regulation and repair. Understanding of how targeting is achieved is still limited, but structures of the histone lysine demethylase JMJD2A in complex with substrate peptides now offer insight into its dual specificity.

Small RNAs can silence target genes by a variety of pathways and mechanisms. Specific microRNAs have now been shown to partition into distinct effector complexes, which may in turn affect their silencing output.