Volume 20 Issue 1, January 2013

Chromatin-remodeling enzymes use the energy from ATP hydrolysis to mobilize, disrupt or change the histone composition of nucleosomes, facilitating nearly every nuclear event. Two recent studies indicate that remodeling enzymes harness the power of an ancient constitutively active DNA translocase and that different remodeling enzymes may use specialized coupling domains that communicate the presence of nucleosomal epitopes to regulate translocase and remodeling activity.

Peptide loading of major histocompatibility complex (MHC) class II molecules in the endosomes and lysosomes of antigen-presenting cells is catalyzed by human leukocyte antigen-DM (HLA-DM) and modulated by HLA-DO. In a structural study in this issue, Guce et al. show that HLA-DO is an MHC class II mimic and functions as a competitive and essentially irreversible inhibitor of HLA-DM activity, thereby inhibiting MHC class II antigen presentation.

Three recent studies converged on a specific protein-protein interface between TPP1 and telomerase as being crucial for the regulation of both telomerase recruitment and processivity in mammalian cells. An equivalent interaction appears to exist in budding yeast, making this a nearly universal means of telomerase regulation.

Nucleosome assembly is crucial for the maintenance of genome stability and epigenetic information and is aided by histone chaperones. This Review discusses recent insights into the mechanisms and roles of histone chaperones in regulating nucleosome assembly and how alterations in nucleosome-assembly factors may be implicated in human diseases.

The eukaryotic ribosome-associated complex (RAC) chaperone is poorly understood. Structural analyses now provide insight into the catalytic inactivity and possible functions of the Ssz1 subunit and reveal that RAC interacts with the ribosome via the Zuo1 subunit. RAC crouches over the ribosomal exit tunnel, where its conformation may be controlled by the ribosomal expansion segment ES27.

Histone chaperone RbAp48 interacts with histones H3–H4 and delivers them to a second histone chaperone, ASF1, to be assembled into new nucleosomes. These interactions are now investigated, revealing that RbAp48 binds H3–H4 heterodimers (but not tetramers) and causes conformational changes in their core fold. Moreover, an allosteric mechanism facilitates exchange of H3–H4 between RbAp48 and ASF1.

A cell-based screen for intronic splicing silencers revealed ten sequence motifs that inhibited splicing in human cells and either enhanced or inhibited exon inclusion when inserted into exons. Identification of trans-acting splicing factors for each motif revealed a complex network, which suggests that cis elements function differently in distinct cellular contexts, depending on the regulatory factors present.

Post-translational modifications are one way in which GTPase functions can be regulated. Monoubiquitination of Lys147 of Ras has been shown to promote tumorigenesis. New data now indicate that this modification promotes Ras activation by impairing GTP hydrolysis catalyzed by GTPase-activating proteins.

Glucocorticoid receptor (GR) transactivates genes containing the response element GRE. GR can also mediate transrepression of genes by binding to the so-called negative GRE (nGRE). The interaction between GR and nGRE is now revealed by structural and functional approaches, showing that two GR monomers bind nGRE in a unique conformation and with strong negative cooperativity.

The ATG12~ATG5 conjugate promotes the transfer of the ubiquitin-like protein LC3 to phosphatidylethanolamine (PE), a modification required for autophagosome formation. Structural and biochemical analyses reveal the determinants for ATG12~ATG5 binding to ATG16 and the E3 ligase ATG3, and indicate how the conjugate stimulates PE–LC3 formation.

Measles virus hemagglutinin (MVH) can bind to different cell surface receptors in the human host. CD46, the first identified MVH receptor, is used mainly by vaccine strains, whereas clinical strains can use SLAM on macrophages and dendritic cells and nectin-4 on epithelial cells. The crystal structure of MVH in complex with the outermost ectodomain of nectin-4 is now presented, revealing a potential target site for drug development.

The exoribonuclease Eri1 binds the stem-loop of histone mRNAs, but the functional significance of this interaction has been unclear. New studies now indicate that 3A oligouridylation of histone mRNAs enables the Lsm1–7 complex to bind the oligo(U) tail and to interact with Eri1, whose catalytic activity degrades the double-stranded stem-loop structure.

Previous work has implied that the ATPase domain of ISWI chromatin remodelers cooperates with a DNA-binding accessory domain to achieve remodeling. Quantitative biochemical analyses now reveal that the ATPase domain exists in two conformations and that DNA binding induces the catalytically active conformation. The ATPase domain has an intrinsic ability to bind and remodel nucleosomes, which suggests that it acts autonomously.

HLA-DM interacts with MHCII and promotes peptide exchange. This activity of HLA-DM is regulated by HLA-DO. The crystal structure of the HLA-DO–HLA-DM complex along with mutagenesis and kinetic analyses reveal that HLA-DO adopts a classical MHCII structure and competitively inhibits HLA-DM's activity on MHCII.

The transmembrane export apparatus regulates protein secretion through bacterial type III secretion systems. New structural data indicate that MxiA, a major component of the apparatus, assembles in a nonameric ring. This and additional structural information provide a framework for understanding how protein secretion is controlled.

Dengue virus has two membrane proteins, E and M, which undergo dramatic structural changes during the life cycle of the virus. The 3.5-Å cryo-EM structure of the mature prefusion Dengue virion reveals the detailed interactions between E and M, providing insight into how conformational changes are triggered.

Formins regulate actin nucleation and filament elongation through their conserved FH2 domain. The formin FMNL3 induces assembly of filopodia, and now the crystal structure of its FH2 domain in complex with actin, together with functional analyses, provides insight into formin's activities.

A comprehensive metagenomic analysis of chromatin immunoprecipitation–sequencing and microarray analysis (ChIP-seq and ChIP-chip) data from mouse embryonic stem cells provides insight into how histone gene transcription is controlled. The work reveals a complex mode of regulation, with multiple factors acting to regulate transcription of core and linker histones.

mRNA-binding proteins have crucial regulatory functions in gene expression. A global analysis in budding yeast now uncovers 120 proteins that cross-link to mRNA, including 66 new mRNA-binding proteins. CLIP analyses of P-body components further identify sites of interaction on specific mRNAs, revealing principles by which these proteins assemble into P-body mRNPs.