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RNA-binding proteins are key regulators of gene expression, yet only a small fraction have been functionally characterized. Here we report a systematic analysis of the RNA motifs recognized by RNA-binding proteins, encompassing 205 distinct genes from 24 diverse eukaryotes. The sequence specificities of RNA-binding proteins display deep evolutionary conservation, and the recognition preferences for a large fraction of metazoan RNA-binding proteins can thus be inferred from their RNA-binding domain sequence. The motifs that we identify in vitro correlate well with in vivo RNA-binding data. Moreover, we can associate them with distinct functional roles in diverse types of post-transcriptional regulation, enabling new insights into the functions of RNA-binding proteins both in normal physiology and in human disease. These data provide an unprecedented overview of RNA-binding proteins and their targets, and constitute an invaluable resource for determining post-transcriptional regulatory mechanisms in eukaryotes. [ABSTRACT FROM AUTHOR]

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health. [ABSTRACT FROM AUTHOR]

Targeting of newly synthesized integral membrane proteins to the appropriate cellular compartment is specified by discrete sequence elements, many of which have been well characterized. An understanding of the signals required to direct integral membrane proteins to the inner nuclear membrane (INM) remains a notable exception. Here we show that integral INM proteins possess basic sequence motifs that resemble ‘classical’ nuclear localization signals. These sequences can mediate direct binding to karyopherin-α and are essential for the passage of integral membrane proteins to the INM. Furthermore, karyopherin-α, karyopherin-β1 and the Ran GTPase cycle are required for INM targeting, underscoring parallels between mechanisms governing the targeting of integral INM proteins and soluble nuclear transport. We also provide evidence that specific nuclear pore complex proteins contribute to this process, suggesting a role for signal-mediated alterations in the nuclear pore complex to allow for passage of INM proteins along the pore membrane. [ABSTRACT FROM AUTHOR]

The faithful inheritance of genetic information, which is essential for all organisms, requires accurate DNA partition (segregation) at cell division. In prokaryotes, partition is mediated by par systems, for which the P1 plasmid system of Escherichia coli is a prototype comprising a partition site and two proteins, ParA and ParB. To form the partition complex necessary for segregation, P1 ParB must recognize a complicated arrangement of A-box and B-box DNA motifs located on opposite ends of a sharply bent parS partition site of ∼74 bp (refs 3–7). Here we describe structures of ParB bound to partition sites. ParB forms an asymmetric dimer with extended amino-terminal HTH (helix–turn–helix) domains that contact A-boxes. The two HTH domains emanate from a dimerized DNA-binding module composed of a six-stranded β-sheet coiled-coil that binds B-boxes. Strikingly, these individual DNA-binding modules rotate freely about a flexible linker, enabling them to contact several arrangements of A- and B-boxes. Most notably, each DNA-binding element binds to and thus bridges adjacent DNA duplexes. These unique structural features of ParB explain how this protein can bind complex arrays of A- and B-box elements on adjacent DNA arms of the looped partition site. [ABSTRACT FROM AUTHOR]

Presents information on a study which determined the involvement of proteins SUV39H1 and HP1 in the repression of euchromatic genes by retinoblastoma protein. Methods; Results; Discussion.

Presents a study which showed that a reduction in protein crowding achieved by the hemizygous knockout of rhodopsin in transgenic mice accelerates the rising phases and recoveries of flash responses. Research methodology; Results and discussion; Conclusions.

Reports the identification of coenzyme Q (ubiquinone) as an obligatory cofactor for uncoupling protein (UCP) function. Insight from the failure of UCP1 expressed in Escherichia coli inclusion bodies to carry out fatty-acid-dependent H[sup]+ transport activity inclusion bodies; Sensitivity of H[sup]+ transport to purine nucleotides, and activation only by oxidized but not reduced coenzyme Q.

Presents a study which reports the solution structure of the spruce budworm (Choristoneura fumiferana) antifreeze protein and characterizes its ice-binding properties. Beta-helix structure of the protein; Comparison to the three known fish antifreeze protein structures; Support for the model by ice crystal morphology and ice-etching experiments; Implications for an explanation of the greater activity of the spruce budworm antifreeze.

Reports a study which describes three voltage-gated potassium channel-interfacing proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha subunits. Function of potassium currents operating at threshold membrane potentials in the brain and heart; How KChIP and Kv4 work together to modulate the density, inactivation kinetics and rate of recovery in heterologous cells; Effects of changes in intracellular calcium on neuronal excitability.

Reports that symbiotic nitrogen-fixing root nodules on legumes are founded by root cortical cells. How the cells de-differentiate and restart cell division to establish nodule primordia; Role of endocytosis in nodule function; Details of plant control of the process; Role of proteins.

Reports attempts to determine functional relationships among proteins of the yeast Saccharomyces cerevisiae. How proteins were grouped; Discovery of 93,000 pairwise links between functionally related yeast proteins; Examples of functional links and the resulting general function assignments.

Presents a study investigating the role of the protein Bid in vivo by generating mice deficient Bid. Role of Bid in the pathway that leads to cell death (apoptosis), mediating the release of cytochrome c from mitochondria in response to signals from death receptors known as TNFR1/Fas on the cell surface; Results of the study; Interpretation.

Presents a study to show the role of molecular chaperones in assisting the folding of newly synthesized proteins in the cytosol. Experiment on Escherichia coli; Methods; Results; Interpretation.

Presents a research on the mechanism of action of the Bacillus subtilis response regulator Spo0F, exploring the relationship between the motional characteristics and protein-protein interactions. Use of a set of nuclear magnetic resonance N relaxation measurements to determine the relative timescales of Spo0F backbone fluctuations on the picosecond-to-millisecond timescale; Demonstration that regions having motion on the millisecond timescale correlate with residues and surfaces that are known to be critical for protein-protein interactions.

Presents research which concluded that Eph protein receptors and ephrins regulate two aspects of cell behavior that can stabilize the identity of adjacent cell populations. Role of Eph proteins in cell interactions; Conserved cytoplasmic tyrosine residues of ephrin-B proteins; Expression of Eph in embryogenesis; Previous research; Observation of bidirectional or unidirectional signaling.

Presents research which showed that the separating protein Esp1 causes the dissociation of the subunit Scc1 from chromosomes. Cohesion between sister chromatids during DNA replication; Role of cohesin; Effects of the attachment of sister kinetochores to the mitotic spindle during mitosis; Importance of cohesion; Study of Saccharomyces cerevisiae; Esp1 and cleavage by proteolysis; Traits of mutant Scc1; Speculation about the evolutionary conservation of separins.

Presents research which showed that the apoptotic activity of the protein p73-alpha requires the presence of the tyrosine kinase c-Abl. Activation of c-Abl; Induction of apoptosis by p73 and p53; Assocation of p73 with c-Abl; Mediation of binding between p73 and c-Abl; Phosphorylation of p73; Pro-apoptotic signaling pathway involving p73 and c-Abl.

Presents research which showed that the GLI protein family member TRA-1 can act post-transcriptionally to govern gene activity. Role of the GLI protein family in developmental processes in vertebrates and invertebrates; Previous research; Effects of binding TRA-1; GLI family members as regulators of gene expression.

Presents research which showed that the amount of the p73 protein in a cell is increased by the cancer chemotherapeutic agent cisplatin. How such agents function; Activation of apoptosis by the gene p53; Induction of p73; p73's half-life; Traits of mutated p73 in mice; Cisplatin-induced cytotoxicity and the roles of p73 and the tyrosine kinase c-Abl.

Presents research which showed that the tyrosine kinase c-Abl binds to the protein p73 in cells. Location of the binding; Role of p73; Activation of c-Abl; How c-Abl phosphorylates p73; c-Abl stimulating p73-mediated transactivation and apoptosis; Regulation of p73 by c-Abl; Effects of p73 in the apoptotic response to DNA damage.

Presents research which studied the role of the protein tau in Alzheimer's disease. The neurofibrillary tangle of paired helical filaments (PHFs) composed of tau; Hyperphosphorylation and phosphorylation of tau; Binding site for the WW domain of the prolyl isomerase Pin1; Effects of Pin1 on mitosis; Depletion of soluble Pin1 in Alzheimer's patients, and its effects; Value of research.

Presents research which identified the cellular factor that participates in viral DNA replication. DNA replication in mammalian viruses; Role of the human papillomavirus (HPV) E1 protein; Use of a two hybrid assay in Saccharomyces cerevisiae and E1 protein; Isolation and role of Ini1/hSNF5; Results of in vitro binding and immunoprecipitation of E1; Revelations from transient DNA-replication assay; Effects of amino-acid substitution at residues that are conserved among E1 proteins.

Presents research which showed that the recombinant proteins Bax and Bak accelerate the opening of the voltage-dependent anion channel (VDAC) in cells. Alteration of mitochondria in the apoptotic signal's transduction; Translocation of the protein cytochrome c in apoptosis; Role of caspases; Regulation of apoptosis by the Bcl-2 proteins; Traits of VDAC1-deficient mitochondria; Binding by Bcl-2 proteins to the VDAC.

Presents research which studied the E1A zinc-finger domain of adenovirus E1A proteins. Role of these proteins in host cells for viral replication; Interaction of E1A proteins with cellular regulatory proteins; Effect of E1A proteins on the transcription of viral early genes; Interaction with the human homologue of Caenorhabditis elegans SUR-2; Stimulation of transcription by the human Srb/Mediator complex.

Presents research which demonstrated the role of the von Hippel-Lindau (VHL) tumor suppressor gene product pVHL in hypoxia-inducible factor-1 (HIF-1) regulation. Role of HIF-1 in cellular responses to hypoxia; Degradation of the alpha subunits of HIF; Traits of VHL-defective cells; Effects of re-expression of pVHL; Iron dependency of HIF-1 and pVHL interactions; HIF-1 activation underlying the angiogenic phenotype of VHL-associated tumors; Application to cellular oxygen sensing studies.

Presents research which showed that the T-box genes Tbx4 and Tbx5 are regulators of limb outgrowth in chicks. Genes associated with fibroblast growth factor (FGF), bone morphogenic protein (BMP), and Wnt; Role of Pitx1 genes in embryonic development; Control of limb identity by Tbx4 and Tbx5.

Presents research which concluded that the protein FLASH is necessary for the activation of caspase-8 in Fas-mediated apoptosis. Role of Fas in cell-death signaling; Activation of Fas; Sequence of FLASH, and its similarity with CED-4 from Caenorhabditis elegans; Stimulated Fas binding FLASH; Effects of the expression and overexpression of FLASH.

Presents research which showed that human protein Rad52 binds directly to double-strand breaks (DSB) in DNA, protects DSBs from exonuclease attack, and facilitates end-to-end interactions. Cause of DSBs; Role of Rad52 and Ku proteins in DNA repair; Results of biochemical studies; Proposed model for DNA repair; Contribution of homologous recombination to vertebrate DSB repair.

Presents research which concluded that the mammalian proteins Cry1 and Cry2 are essential for the maintenance of circadian rhythmicity. Models for biological clocks; Oscillation of molecular clocks; Study of mice lacking the proteins; Mice showing a sudden and complete loss of rhythmicity.

Presents research which studied the role of dynamin in receptor-mediated endocytosis. Dynamin a GTP-hydrolyzing protein; Dynamin's self-assembly; GTPase activity by dynamin; Dynamin's hydrolysis of GTP; Effects of the overexpression of dynamin mutants; Dynamin not behaving like a force-generating GTPase.

Presents research which used Xenopus embryos to show that Wnt-inhibitory factor-1 (WIF-1) overexpression affects somitogenesis. Role of Wnt proteins in developmental processes; Animals in which WIF-1 is present; Binding by WIF-1; Interaction of Wnt proteins with extracellular inhibitors.

Presents research which showed that the misexpression of the protein Short gastrulation (Sog) redistributes Decapentaplegic (Dpp) signaling in the Drosophila embryo. Effect of Dpp on Drosophila development; Role of the protein Tolloid (Tld); Diminishment or increase of Dpp activity; Importance of the diffusion of Sog; Role of the inhibitor Noggin.

Presents research which showed that the Rad24 protein controls the intracellular distribution of the mitotic inducer Cdc25. DNA damage activating a cell cycle checkpoint; Role of the protein Chk1; Effects of phosphorylation of Cdc25 by Chk1; Effects of the activation of the DNA-damage checkpoint; Impact of a mutation in Rad24; Rad24's function in the nuclear export of Cdc25.

Presents research which identified the cellular protein GABA A-receptor-associated protein (GABARAP), which interacts with the gamma-2 subunit of GABA A receptors. Type-A receptors for GABA; Traits of the subunits of receptor proteins; Positioning of neurotransmitter receptors; Binding by GABARAP; Results of sequence analysis; The N terminus of GABARAP; Mechanism for the targeting and clustering of GABA A receptors.

Presents research which showed that mutations in Su(fu) cause an increase in the expression of Hh-target genes while reducing Cubitus interruptus-155 (Ci-155) concentration. Study of Drosophila; Impact of signaling by the protein Hedgehog (Hh) on the transcription factor Cubitus interruptus; Location of Ci-75 and Ci-155; Effects of eliminating Fu kinase activity; Requirement of Fu kinase activity for Hh to stimulate maturation of Ci-155.

Presents research which studied the role of a protein called postsynaptic density-95 (PSD-95) in mice synapses. Changes in synaptic strength related to learning and memory; Patterns of neuronal firing; Effects of the blockage of postsynaptic NMDA receptors; Binding by the NMDA receptor; Traits of mutant mice lacking PSD-95; Consistency of findings with neural network models incorporating bidirectional learning rules.

Presents research which studied the mammalian Htrp3 protein and the effect of Ca2+ store depletion on store-operated channels (SOCs) and the Ca2+-release-activated current (Icrac). Release of calcium ions from intracellular stores; Effects of the depletion of Ca2+; Models of cell signaling; Expression of Htrp3 channels in HEK293 cells; Activation of Htrp3 channels by InsP3; Evidence for the coupling hypothesis.

Presents research which described the crystal structure of titin's catalytic domain, an autoregulated serine kinase. Role of titin in control of sarcomere assembly; Inhibition by a tyrosine; Dual mechanism of activation of titin kinase; Serine kinase domain of titin; Location of phosphorylated tyrosine; Phosphorylation of titin kinase; Kinase's action in myofibrillogenesis.

Presents research which showed that membrane microdomains of a glycosyl-phosphatidyl-inositol (GPI)-anchored protein exist at the surface in living cells. Role of GPI-anchored proteins in processes and complexes; Use of chemical crosslinking; How clustering is specific; Effects of the depletion of membrane cholesterol; Size of microdomains.

Presents research which studied the function of the endocytosis accessory factor Eps15. Role of clathrin and the clathrin adaptor protein AP-2 in endocytosis; Role of the protein epsin; Epsin with Eps15 in presynaptic nerve terminals; Epsin binding; Epsin and clathrin coats in situ; Disruption of epsin function.

Presents research which identified a new Drosophila gene called tout-velu that is required for diffusion of Hedgehog (Hh) proteins. Role of Hh in invertebrate and vertebrate development; Characterization of tout-velu; Tout-velu part of the EXT gene family; Suggestion that multiple exostoses syndrome is associated with abnormal diffusion of Hh proteins; New conserved mechanism for diffusion of Hh.

Presents research which showed that mice lacking the Mxi1 protein exhibit progressive, multisystem abnormalities. Mxi1 an antagonist of Myc oncoproteins; Possibility that Mxi1 is a tumor-suppressor gene; Chromosomal location of gene; Traits of mice; Proliferative ability of Mxi1-deficient cell types; Role of Mxi1.

Presents research which studied the mechanism of gene repression by the protein MeCP2. Effects of cytosine-guanine (CpG) methylation; Role of MeCP2 in mouse embryogenesis; MeCP2 binding; MeCP2's transcriptional-repression domain (TRD); MeCP2 associating with a corepressor complex; Transcriptional repression in vivo; Two mechanisms of gene regulation linked by MeCP2.

Presents research which reported the functional differences of the related proteins p300 and CBP in vivo. Role of these proteins in gene expression, cell differentiation and signal transduction pathways; Conditions under which the proteins' roles were studied; Use of hammerhead ribozymes; Expression in F9 cells; Ribozymes blocking retinoic-acid-induced apoptosis; Distinct functions of p300 and CBP.

Presents research which showed that the fission yeast telomere protein, Taz1, is required for stable association between telomeres and spindle pole bodies during meiotic prophase. Importance of alignment of homologous chromosomes during meiosis; Role and composition of telomeres; Effects of absence of Taz1; Importance of telomeric association mediated by telomere-specific proteins.

Presents research which identified the gene responsible for early-onset, diffuse gastric cancer. Prevalence of gastric cancer; Familial incidence of gastric cancer; Study of a large kindred from New Zealand; Results of genetic linkage analysis; Sequencing of the E-cadherin protein gene; Effects of diminished E-cadherin expression; Role of E-cadherin in gastric cancer; Molecular basis for gastric cancer.

Presents research which studied isomerization in the photoactive yellow protein (PYP). Protein photosensors and chromophores in light detection; Isomerization of a double bond in each chromophore; How the 4-hydroxycinnamoyl chromophore isomerizes; Presence of protein-to-chromophore hydrogen bond; Distortion of isomerized bond; Use of resultant stored energy; Model for phototransduction; Implications of research.