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Receptor downregulation in the MVB pathway is mediated by the ESCRT complexes. ESCRT-III is composed of four protein subunits that are monomeric in the cytosol and oligomerize into a protein lattice only upon membrane binding. Recent studies have shown that the ESCRT-III protein Snf7 can form a filament by undergoing homo-oligomerization. To examine the role of membrane binding and of interactions...
In the fruit fly Drosophila, not all olfactory sensory neurons express a seven transmembrane odorant receptor, suggesting that other types of odorant receptors might exist. Benton et al. (2009) now present evidence that a family of proteins related to ionotropic glutamate receptors is a previously unrecognized class of odorant receptors.
The ESCRT-III complex mediates membrane budding away from the cytosol in endosome biogenesis, cytokinesis, and viral budding. In this issue, Saksena et al. (2009) use an elegant fluorescence-based approach to define the sequential activation, recruitment, and disassembly of ESCRT-III subunits during membrane involution in vitro.
Smad4 is an important mediator of signaling by TGFβ family members that is presumed to be controlled by the phosphorylation status of its partners, the receptor-regulated R-Smads. In this issue, Dupont et al. (2009) now reveal that Smad4 itself is subject to cycles of ubiquitination and deubiquitination that regulate its interactions with the R-Smads.
MicroRNA (miRNA) control has emerged as a critical regulatory principle in the mammalian immune system. Genetic ablation of the miRNA machinery, as well as loss or deregulation of certain individual miRNAs, severely compromises immune development and response and can lead to immune disorders like autoimmunity and cancer. Although individual miRNAs modulate protein output from hundreds of target genes,...
Eukaryotic DNA is bound and interpreted by numerous protein complexes in the context of chromatin. A description of the full set of proteins that regulate specific loci is critical to understanding regulation. Here, we describe a protocol called proteomics of isolated chromatin segments (PICh) that addresses this issue. PICh uses a specific nucleic acid probe to isolate genomic DNA with its associated...
Both the sirtuins and certain transcription factors of the NF-κB/Rel family control aging-associated changes in gene expression. Kawahara et al. (2009) now show a requirement in mice for the sirtuin SIRT6 in dampening NF-κB-dependent gene expression, thus unveiling a potential link between inflammation, aging, and metabolism.
Condensins are key mediators of chromosome condensation across organisms. Like other condensins, the bacterial MukBEF condensin complex consists of an SMC family protein dimer containing two ATPase head domains, MukB, and two interacting subunits, MukE and MukF. We report complete structural views of the intersubunit interactions of this condensin along with ensuing studies that reveal a role for...
Ionotropic glutamate receptors (iGluRs) mediate neuronal communication at synapses throughout vertebrate and invertebrate nervous systems. We have characterized a family of iGluR-related genes in Drosophila, which we name ionotropic receptors (IRs). These receptors do not belong to the well-described kainate, AMPA, or NMDA classes of iGluRs, and they have divergent ligand-binding domains that lack...
Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy...
In plants, G proteins modulate signaling by the stress hormone, abscisic acid (ABA). We identify and characterize two novel Arabidopsis proteins that show homology to an orphan vertebrate GPCR (GPR89) and interact with the sole Arabidopsis G protein α subunit, GPA1, but also have intrinsic GTP-binding and GTPase activity. We have named these proteins GPCR-type G proteins (GTG1 and GTG2). Arabidopsis...
Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-κB signaling. SIRT6 interacts with the NF-κB RELA subunit and deacetylates histone...
By investigating host-pathogen interactions in zebrafish using intravital imaging, Davis and Ramakrishnan (2009) provide evidence that aggregates of immune cells known as granulomas, long thought to constrain mycobacterial infection, may instead facilitate its spread.
Segregation of nonexchange chromosomes during Drosophila melanogaster meiosis requires the proper function of NOD, a nonmotile kinesin-10. We have determined the X-ray crystal structure of the NOD catalytic domain in the ADP- and AMPPNP-bound states. These structures reveal an alternate conformation of the microtubule binding region as well as a nucleotide-sensitive relay of hydrogen bonds at the...
The assembly of the Smad complex is critical for TGFβ signaling, yet the mechanisms that inactivate or empower nuclear Smad complexes are less understood. By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFβ and bone morphogenetic protein signaling. Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that...
Mitochondria are mobile organelles and cells regulate mitochondrial movement in order to meet the changing energy needs of each cellular region. Ca 2+ signaling, which halts both anterograde and retrograde mitochondrial motion, serves as one regulatory input. Anterograde mitochondrial movement is generated by kinesin-1, which interacts with the mitochondrial protein Miro through an adaptor...
The stem cell field is gradually moving toward translational applications as exemplified by the papers highlighted in this Stem Cell Select. In vitro human embryonic stem cell (hESC) models of disease may prove useful for drug screening. Resolving whether cancer stem cells are important for the pathogenesis of all or only some human cancers should accelerate development of new stem cell-specific therapeutic...
The Drosha-DGCR8 complex, also known as Microprocessor, is essential for microRNA (miRNA) maturation. Drosha functions as the catalytic subunit, while DGCR8 (also known as Pasha) recognizes the RNA substrate. Although the action mechanism of this complex has been intensively studied, it remains unclear how Drosha and DGCR8 are regulated and if these proteins have any additional role(s) apart from...
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