Articles in 2008

Channel gating in tetrameric cation channels occurs as structural transitions that involve straightening and bending of inner helices at a conserved glycine residue. Structural representatives of these closed and opened states have come from crystal structure of KcsA and MthK, respectively. The structure of NaK in the open state, when combined with a previously determined structure of NaK in the closed state, allows the detailed analysis of channel gating within the same channel.

The negatively coupled movement of the activation and inactivation gates of Kv channels regulates ion flow across membranes in response to changes in membrane potential. Although they share a common pore design, the K_2P leak channels are open at all potentials and are believed to act only through a slow inactivation gate. New data reveal that, similarly to the Kv channels, leak channels possess a constitutively open lower activation gate. Positive coupling between the two gates ensure constant leak currents across the membrane.

Although a number of DExD/H-box family RNA-dependent ATPases are required in the spliceosome, their regulation is unclear. The Brr2-dependent unwinding of U4/U6 snRNAs, a key step in splicing, is now shown to be promoted in a purified system by the C-terminal region of Prp8, an enigmatic spliceosome component associated with a dominant form of retinitis pigmentosa.

Ion selectivity is as important to ion channel function as channel gating. Much of what is currently known about selectivity comes from structural studies of K⁺-selective channels. Detailed structural analysis of the ion binding sites in the NaK pore provides a first look at the geometry and ionic selectivity in a Na⁺-permeable channel and may provide a basis for understanding permeation through nonselective cation channels.

Type I restriction-modification enzymes recognize a target sequence and translocate DNA from both sides while remaining stationary, creating supercoiled loops and cleaving at nonspecific sites several kilobases away. The crystal structure of the motor subunit of EcoR124I is now solved, providing insight into these complex machines.

Plants contain atypical RNA polymerases that have been implicated in RNA silencing. An analysis of RNA polymerase V composition now reveals that it unexpectedly shares some, but not all, subunits found in RNA polymerase II, indicating that it may be a derived version of this polymerase complex. Additional subunits are also identified and implicated in RNA-mediated silencing.

TIPE2 is involved in immune homeostasis, and it has been assumed that it contained a death effector domain (DED). Now the crystal structure of TIPE2 reveals that it does not possess a DED, but instead has a previously uncharacterized fold, with a large central cavity that might accommodate a ligand.

The transcription factor and tumor suppressor p53 is central to many stress responses and is the target of multiple regulators. The regulatory subunit of PI3 kinase, p85α and CDC42 are now both found to be targets of the miR-29 microRNAs. As p85α and CDC42 are repressors of p53, these miRNAs indirectly activate p53 and thus apoptosis.

Nucleosome stability can influence gene expression and is regulated by nucleosome-positioning sequences, histone chaperones, remodeling complexes, post-translational modifications and histone variants. Now, histone H3 tail clipping has been added to the list. Kouzarides and co-workers have identified a serine endopeptidase in yeast that cleaves H3 after Ala21 and shows a preference for H3 tails with repressive modifications. In vivo, this occurs at the promoters of induced genes and precedes histone eviction when genes become fully active.

Nonsense-mediated decay (NMD) is an mRNA surveillance process that targets transcripts containing a premature stop codon for degradation. Evidence now suggests that mammalian NMD involves an endonucleolytic cleavage that is mediated by human SMG6.

The exosome is a large complex with cellular functions including exoribonucleolytic mRNA degradation and processing of a number of RNAs including small nuclear RNAs, small nucleolar RNAs and ribosomal RNAs. The yeast exosome is now shown to possess an unexpected endoribonucleolytic activity, and the essential Csl4 subunit is shown to contain a domain involved in mRNA decay. This suggests that particular domains in the complex have specialized roles.

NSMB observes World AIDS Day by reflecting on the crucial role of basic research in fighting this epidemic.

New work suggests that Prp8, a highly conserved protein in the heart of the spliceosome, both orients the substrate and participates in catalysis.

The tumor suppressor protein 53BP1 decorates DNA damage sites and is instrumental for nonhomologous end joining. Evidence that 53BP1 facilitates synapsis of DNA ends by modulating chromatin dynamics reveals a hitherto unanticipated strategy for joining distant ends.

A recent report shows that several 'poly-ADP-ribose-polymerases' may function exclusively as a family of endogenous mono-ADP-ribosyltransferases, providing a new, molecularly less complex and broadened cellular role for this elusive post-translational modification.

Analysis of in vivo and in vitro interactions between chaperonins and the whole spectrum of potential cytoplasmic substrates helps answer the vexed question of substrate specificity in the TRiC system.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. The N-end rule pathway, ubiquitin-dependent in eukaryotes, is also present in prokaryotes, which lack the ubiquitin system. An illuminating new study presents the crystal structure of a bacterial N-end rule recognition component in complex with a peptide containing a cognate degradation signal.

Muscleblind-like (MBNL) proteins have been implicated in alternative-splicing regulation during development, and altered levels of these proteins have been implicated in myotonic dystrophy. The structure of the MBNL1 zinc finger domains in complex with RNA indicates how the target sequence is recognized and suggests that an antiparallel arrangement of the zinc fingers causes a trajectory reversal in the pre-mRNA target. The potential role of such generated looped segments in alternative splicing is discussed.

PKR responds to viral infection and shuts down translation through phosphorylation of eIF2α. PKR is found to have rapidly evolved in comparison to other kinases targeting the same substrate across a broad range of vertebrate lineages. Some positively selected residues are found to confer resistance to poxviral inhibitors that mimic substrate. In addition, substituting a single residue in mouse PKR with the corresponding residue under positive selection in human PKR renders mouse PKR more resistant to K3L and vice versa, providing evidence for species-specific selection driven by beneficial mutations.