Brief Communications in 2009

Helicobacter pylori is a strong risk factor for stomach cancer. The CagA effector protein is translocated into host cells by a type IV secretion system and is a key virulence factor. Its effects are mediated in part through the host polarity kinase PAR1b/MARK2, which CagA binds and inhibits. The crystal structure of a complex between CagA peptide and MARK2 reveals that the CagA peptide mimics targets of this kinase family.

The TAK1 kinase binds K63-linked ubiquitin specifically via its TAB2 subunit. The structure of the TAB2 NZF domain in complex with K63-linked ubiquitins now indicates that this domain interacts with neighboring ubiquitins through distinct sites, explaining the basis of specific recognition.

De novo methylation of DNA can affect the function of underlying genes and transposons in plants. Using a genetic screen, two factors required for de novo demethylation in Arabidopsis thaliana are identified and analyzed.

Phage lysis requires the enzymatic degradation of the host cell wall by a phage-encoded lysin. Secretory endolysins are inactive at the membrane but active in the cytoplasm, and the signal-anchor-release (SAR) domain is shown to be essential for regulating its effects. The structure of coliphage 21 lysozyme explains how this endolysin is controlled.

The poxvirus 2L protein binds tumor necrosis factor-α (TNFα). Structural data now indicate that 2L interacts with TNFα at a site overlapping with that for its receptor, arguing for the basis of inhibition of receptor interaction and TNFα-induced immune responses.

Sialic acid is the most abundant terminal monosaccharide on mammalian cell surface glycoconjugates. The crystal structures of a mammalian sialyltransferase, that of porcine ST3Gal-I, in the apo form and bound to analogues of the donor and acceptor substrate are now described, providing insights into the catalytic mechanism and for inhibitor design.

The anaphase promoting complex (APC) is a key cell-cycle regulator that has ubiquitin-ligase activity. The first structure of a complex formed between APC subunits, that of CDC26 and APC6, provides detailed structural information of APC components and suggests how CDC26 may stabilize APC6 and other complex subunits.

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.

WAVE proteins in the WASP family are controlled by incorporation into the WAVE regulatory complex (WRC), which transmits information from the Rac GTPase to the actin cytoskeleton. By reconstituting human and fly WRCs, the native complex is shown to be inactive. Rac activates the WRC, but does not cause subunit dissociation. These results reconcile previous work and reveal common regulatory principles for the WASP family.

The nuclear transport receptor CRM1 mediates protein export from the nucleus through recognition of leucine-rich nuclear export signals on substrates. Structural analysis, based in part on the recent structure of a CRM1-SNUPN complex, reveal determinants for substrate binding and suggest a mechanism for binding partner-assisted dissociation of SNUPN in the cytoplasm.

BMAL1 has a central role in the mammalian circadian clock, acting as a transcriptional activator. The activity of BMAL1 is controlled by post-translational modifications such as acetylation and SUMOylation. Now the kinase CK2a is shown to phosphorylate BMAL1 at Ser90, and this is essential for BMAL1's function in the circadian clock.

Methylation at particular residues on histone tails has been associated with various functions and, in the case of dimethylated histone H3 arginine 2 (H3R2), cross-talk with methylation of a nearby lysine has been shown to be linked to transcriptional repression. Budding yeast monomethylated H3R2 is now shown to be associated with active loci and involved in activation of meiotic genes upon induction of sporulation.

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.

Expanded CGG repeats cause chromosomal fragility and hereditary neurological disorders in humans. These repeats adopt unusual structures that block DNA replication in vitro and in unicellular organisms. Mirkin and co-workers asked whether the same holds true in mammalian cells. They find that CGG repeats stall replication forks in a length-dependent, but orientation-independent, manner and do not seem to trigger an intra–S phase checkpoint response. They suggest that fragile sites arise because the cell cycle continues before replication is complete and the under-replicated areas would convert into constrictions and/or double-stranded breaks.

Sortilin is a neuronal receptor involved in sorting and signal transduction. The crystal structure of the mature Sortilin ectodomain bound to one of its ligands, neurotensin, reveals a binding tunnel formed by the Sortilin β-propeller domain. Combined with binding and mutagenesis studies, the findings suggest that Sortilin substrates compete for access to the tunnel so that only one ligand binds at a time.