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Muscle contractions are driven by neurotransmitters released at neuromuscular junctions. In this issue, Beg et al. (2008) report that protons, in the absence of neurotransmitters and neurons, can stimulate muscle contractions involved in the defecation cycle of the worm Caenorhabditis elegans. Their results identify protons as a new intercellular messenger and suggest that proton-mediated intercellular...
Muscle contraction is normally mediated by the release of neurotransmitters from motor neurons. Here we demonstrate that protons can act as a direct transmitter from intestinal cells to stimulate muscle contraction. During the C. elegans defecation motor program the posterior body muscles contract even in the absence of neuronal inputs or vesicular neurotransmission. In this study, we demonstrate...
MicroRNAs are ∼22 nucleotide-long RNAs that silence gene expression posttranscriptionally by binding to the 3′ untranslated regions of target mRNAs. Although much is known about their biogenesis and biological functions, the mechanisms allowing miRNAs to silence gene expression in animal cells are still under debate. Here, we discuss current models for miRNA-mediated gene silencing and formulate a...
The structure of the E. coli β clamp polymerase processivity factor has been solved in complex with primed DNA. Interestingly, the clamp directly binds the DNA duplex and also forms a crystal contact with the ssDNA template strand, which binds into the protein-binding pocket of the clamp. We demonstrate that these clamp-DNA interactions function in clamp loading, perhaps by inducing the ring to close...
Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis. Autophagy principally serves an adaptive role to protect organisms against diverse pathologies, including infections, cancer, neurodegeneration, aging, and heart disease. However, in certain experimental disease settings, the self-cannibalistic or, paradoxically, even the prosurvival...
It remains unclear how misfolded membrane proteins are selected and destroyed during endoplasmic reticulum-associated degradation (ERAD). For example, chaperones are thought to solubilize aggregation-prone motifs, and some data suggest that these proteins are degraded at the ER. To better define how membrane proteins are destroyed, the ERAD of Ste6p ∗ , a 12 transmembrane protein, was reconstituted...
Proper distribution of mitochondria within axons and at synapses is critical for neuronal function. While one-third of axonal mitochondria are mobile, a large proportion remains in a stationary phase. However, the mechanisms controlling mitochondrial docking within axons remain elusive. Here, we report a role for axon-targeted syntaphilin (SNPH) in mitochondrial docking through its interaction with...
In prokaryotes, the toxin-antitoxin systems are thought to play important roles in growth regulation under stress conditions. In the E. coli MazE-MazF system, MazF toxin functions as an mRNA interferase cleaving mRNAs at ACA sequences to inhibit protein synthesis leading to cell growth arrest. Myxococcus xanthus is a bacterium displaying multicellular fruiting body development during which approximately...
Besides their role in desensitization, β-arrestin 1 and 2 promote the formation of signaling complexes allowing G protein-coupled receptors (GPCR) to signal independently from G proteins. Here we show that lithium, a pharmacological agent used for the management of psychiatric disorders such as bipolar disorder, schizophrenia, and depression, regulates Akt/glycogen synthase kinase 3 (GSK3) signaling...
Fast growth of microtubules is essential for rapid assembly of the microtubule cytoskeleton during cell proliferation and differentiation. XMAP215 belongs to a conserved family of proteins that promote microtubule growth. To determine how XMAP215 accelerates growth, we developed a single-molecule assay to visualize directly XMAP215-GFP interacting with dynamic microtubules. XMAP215 binds free tubulin...
The long-awaited structure of the effector portion of IRE1, the endoplasmic reticulum stress transducer, is published in this issue of Cell (Lee et al., 2008). This structure provides new insight into the mysterious coupling of kinase and endoribonuclease activities in the oldest, most-conserved branch of the unfolded protein response in eukaryotes.
Ire1 is an ancient transmembrane sensor of ER stress with dual protein kinase and ribonuclease activities. In response to ER stress, Ire1 catalyzes the splicing of target mRNAs in a spliceosome-independent manner. We have determined the crystal structure of the dual catalytic region of Ire1at 2.4 Å resolution, revealing the fusion of a domain, which we term the KEN domain, to the protein kinase domain...
Caveolae are small membrane invaginations important for cell signaling that are characterized by the presence of caveolin proteins. Hill et al. (2008) have now identified PTRF as a new constituent of the caveolar coat. In the absence of PTRF, caveolae flatten and caveolin-1 is released into the cell membrane, where it is rapidly internalized and degraded.
The recent generation of induced pluripotent stem (iPS) cells from adult human somatic cells has intensified interest in cellular therapies for treating human disease. This issue's Molecular Medicine Select highlights progress in overcoming barriers to the use of transplanted cells. These achievements include the treatment of sickle cell anemia in mice using genetically repaired iPS cells, the creation...
Caveolae are abundant cell-surface organelles involved in lipid regulation and endocytosis. We used comparative proteomics to identify PTRF (also called Cav-p60, Cavin) as a putative caveolar coat protein. PTRF-Cavin selectively associates with mature caveolae at the plasma membrane but not Golgi-localized caveolin. In prostate cancer PC3 cells, and during development of zebrafish notochord, lack...
XMAP215 is a microtubule plus-end binding protein implicated in modulating microtubule dynamics. In this issue, Brouhard et al. (2008) propose a new mechanism to explain how XMAP215 promotes microtubule growth. They report that XMAP215 moves with the growing microtubule plus ends where it catalyzes the addition of tubulin subunits.
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