Articles in 2012

The enzymes involved in autophagy-related UBL conjugation bear only passing resemblance to their counterparts in the better-known UBL conjugation pathways. New structural work provides insight into the mechanism by which the UBL proteins Atg8 and Atg12 are correctly charged by a single activating enzyme, Atg7, then transferred onto their cognate E2 proteins, Atg3 and Atg10, respectively.

Vacuolar-type ATPases (V-type ATPases) are large integral membrane protein complexes. Their activity acidifies intracellular compartments, and they are regulated by the dissociation of the complex's V1 and VO regions. The cryo-EM reconstruction of the yeast V-type ATPase suggests how structural rearrangements triggered by dissociation of V1 leads to inhibition of activity.

Mitotic exit follows shortly after microtubule attachment of the last unattached kinetochore. Two new studies illustrate the molecular basis of this dependency.

According to the 'classical' view, histone modifications are established in an identical fashion on both copies of each of the four core histones, resulting in 'symmetrically' modified nucleosomes. Now, a new study challenges this notion by demonstrating that asymmetric histone modifications exist on individual mononucleosomes in native chromatin and that symmetric and asymmetric modifications signal different biological outcomes, suggesting a radically expanded histone code.

TET and JBP proteins catalyze the oxidation of methylated C bases in the mammalian genome and of the methyl group of T bases in kinetoplastid genomes, respectively. A recent study in Nature Structural & Molecular Biology suggests a new function of 5-methylcytosine oxidation in regulating RNA polymerase II elongation rate that is reminiscent of that of base J in transcription termination in Leishmania.

The number and types of known functional noncoding RNAs (ncRNAs) has increased considerably over the past few years, and both cis- and trans-acting ncRNAs have been reported. This Review focuses on long- and short-sized ncRNAs that act in cis; that is, where both the regulatory RNA and the target gene are transcribed from the same locus.

Methylation of H3K27 by Polycomb repressive complex 2 (PRC2) is essential for gene regulation. A new study provides structural evidence for the recognition of di- and trimethylated H3K36 by the Tudor domain of PRC2 subunit Phf19 as well as functional data suggesting that recognition of di- or trimethylated Phf19–H3K36 is required for regulating PRC2 activity and for full repression of selected PRC2 targets in embryonic stem cells.

Rio2 is an atypical protein kinase required for pre-40S subunit maturation. The crystal structure of eukaryotic Rio2 with bound ATP and Mg²⁺ reveals an unusual phosphoaspartate intermediate typically observed in P-type ATPases. Rio2 has in vitro ATPase activity, and its catalytic activity stimulates its own dissociation from the ribosome, which is required for pre-40S maturation.

DNA-repair enzyme Tdp2 hydrolyzes the 5'-phosphotyrosine bond formed by topoisomerases and is associated with resistance to anticancer drugs that trap such complexes. The crystal structures of zebrafish Tdp2 bound to DNA offer insight into substrate recognition. In addition, the crystal structure of nematode Tdp2 suggests a potential mechanism for autoregulation.

VAMP7 is a SNARE protein involved in the fusion of endosomes and lysosomes with various cellular membranes. The longin domain of VAMP7 forms autoinhibitory interactions that prevent VAMP7 SNARE assembly. New structural and functional data reveal how the regulatory protein Varp, a known VAMP7 binding partner, kinetically inhibits SNARE complex formation.

Semaphorin-plexin cell-cell signaling is important in tissue development, with roles in axon guidance, immunity and cancer. The structure of the complex formed between semaphorin-3, plexin-A and their co-receptor neuropilin, combined with mutagenesis, reveals how neuropilin contributes to stabilizing the signaling complex.

Tyrosyl-DNA phosphodiesterase 2 (Tdp2) processes DNA termini with a 5′-phosphotyrosyl–linked topoisomerase II adduct, such as those stabilized by chemotherapeutic drugs anthracyclines and etoposides, by direct reversal of the 5′-phosphotyrosyl linkage. Now crystal structures of mouse Tdp2–DNA complexes, along with mutagenesis and functional analyses, reveal how Tdp2 recognizes and reverses such adduction.

Microtubules bind to the kinetochore at the Ndc80 complex, and this interaction is regulated by phosphorylation events at the N-terminal tail of Ndc80, mediated by the Aurora B kinase. The distinct functions of Ndc80 N-terminal tail are now dissected, revealing a region that binds tubulin and another that contacts the globular head of Ndc80. Both contacts are disrupted by phosphorylation, and the results lead to a mechanistic model for how phosphorylation of Ndc80 controls its interactions with microtubules.

Tissue- and disease-specific features of nucleosome positioning have recently been reported. A new study set out to identify features of nucleosome positioning at functional genomic elements during lineage commitment from mouse embryonic stem cells to neural progenitors and embryonic fibroblasts. The results reveal regulatory mechanisms of cell differentiation that involve nucleosome positioning.

The exon junction complex (EJC) has a crucial role in various post-transcriptional control mechanisms. CLIP-Seq analysis of the human EJC component eIF4AIII has revealed peaks in canonical EJC-binding regions, including ~24 nucleotides upstream of exon junctions. Surprisingly, EJCs are also present elsewhere in the transcriptome, uncovering an unexpected heterogeneity of EJC association with mRNAs.

Histone H2A.Z-containing nucleosomes flank the transcription start sites (TSSs) of active mammalian genes. A new study reveals that histone H2A.Z at the TSS is reduced during S phase, which coincides with its gain at centromeric and subtelomeric regions during M phase and mirrors an expansion of the nucleosome-depleted region, which, surprisingly, is unrelated to transcriptional activity.

Adenosylcobalamin is a form of vitamin B₁₂ that serves as a coenzyme in different reactions and as a ligand for riboswitches to control bacterial gene expression. The crystal structure of a B₁₂ riboswitch from Symbiobacterium thermophilum bound to its ligand adenosylcobalamin is now presented, revealing the determinants for ligand recognition and gene expression control.