Lateral mobility of β-receptors involved in adenylate cyclase activation

Cationized ferritin was found to inhibit the lateral mobility of intramembrane proteins in turkey erythrocyte membranes and the activation of adenylate cyclase by the (?)-epinephrine-bound β-adrenergic receptor. It was observed that cationized ferritin has only a small direct effect on the β-receptor and on the adenylate cyclase moiety. It is concluded that the cationized ferritin-induced inhibition of the hormone-dependent cyclase activity results from the inhibition of the lateral mobility of the receptor and therefore a decrease in the bimolecular rate of interaction between the receptor and the enzyme.     

InSite: a computational method for identifying protein-protein interaction binding sites on a proteome-wide scale

We propose InSite, a computational method that integrates high-throughput protein and sequence data to infer the specific binding regions of interacting protein pairs. We compared our predictions with binding sites in Protein Data Bank and found significantly more binding events occur at sites we predicted. Several regions containing disease-causing mutations or cancer polymorphisms in human are predicted to be binding for protein pairs related to the disease, which suggests novel mechanistic hypotheses for several diseases.     

Mechanistic insights from a quantitative analysis of pollen tube guidance

Background  

Plant biologists have long speculated about the mechanisms that guide pollen tubes to ovules. Although there is now evidence that ovules emit a diffusible attractant, little is known about how this attractant mediates interactions between the pollen tube and the ovules.     

Macroevolutionary patterns of bumblebee body size: detecting the interplay between natural and sexual selection

Bumblebees and other eusocial bees offer a unique opportunity to analyze the evolution of body size differences between sexes. The workers, being sterile females, are not subject to selection for reproductive function and thus provide a natural control for parsing the effects of selection on reproductive function (i.e., sexual and fecundity selection) from other natural selection. Using a phylogenetic comparative approach, we explored the allometric relationships among queens, males, and workers in 70 species of bumblebees (Bombus sp.). We found hyperallometry in thorax width for males relative to workers, indicating greater evolutionary divergence of body size in males than in sterile females. This is consistent with the hypothesis that selection for reproductive function, most probably sexual selection, has caused divergence in male size among species. The slope for males on workers was significantly steeper than that for queens on workers and the latter did not depart from isometry, providing further evidence of greater evolutionary divergence in male size than female size, and no evidence that reproductive selection has accelerated divergence of females. We did not detect significant hyperallometry when male size was regressed directly on queen size and our results thus add the genus Bombus to the increasing list of clades that have female-larger sexual size dimorphism and do not conform to Rensch's rule when analyzed according to standard methodology. Nevertheless, by using worker size as a common control, we were able to demonstrate that bumblee species do show the evolutionary pattern underlying Rensch's rule, that being correlated evolution of body size in males and females, but with greater evolutionary divergence in males.     

THE EVOLUTION OF THRESHOLD TRAITS: A QUANTITATIVE GENETIC ANALYSIS OF THE PHYSIOLOGICAL AND LIFE-HISTORY CORRELATES OF WING DIMORPHISM IN THE SAND CRICKET

Many traits are phenotypically discrete but polygenically determined. Such traits can be understood using the threshold model of quantitative genetics that posits a continuously distributed underlying trait, called the liability, and a threshold of response, individuals above the threshold displaying one morph and individuals below the threshold displaying the alternate morph. For many threshold traits the liability probably consists of a hormone or a suite of hormones. Previous experiments have implicated juvenile hormone esterase (JHE), a degratory enzyme of juvenile hormone, as a physiological determinant of wing dimorphism in the crickets Gryllus rubens and G. firmus. The present study uses a half-sib experiment to measure the heritability of JHE in the last nymphal stadium of G. firmus and its genetic correlation with fecundity, a trait that is itself genetically correlated with wing morph. The phenotypic and genetic parameters are consistent with the hypothesis that JHE is a significant component of the liability. Comparison of sire and dam estimates suggest that nonadditive effects may be important. Two models have been proposed to account for the fitness differences between morphs: the dichotomy model, which assumes that each morph can be characterized by a particular suite of traits, and the continuous model, which assumes that the associated fitness traits are correlated with the liability rather than the morphs themselves. The latter model predicts that the fitness differences will not be constant but change with the morph frequencies. Variation in fecundity and flight muscle histolysis are shown to be more consistent with the continuous model. Data from the present experiment on JHE are inconclusive, but results from a previous selection experiment also suggest that variation in JHE is consistent only with the continuous model.     

Targeted degradation of ABC transporters in health and disease

ATP binding cassette (ABC) transporters comprise an extended protein family involved in the transport of a broad spectrum of solutes across membranes. They consist of a common architecture including two ATP-binding domains converting chemical energy into conformational changes and two transmembrane domains facilitating transport via alternating access. This review focuses on the biogenesis, and more precisely, on the degradation of mammalian ABC transporters in the endoplasmic reticulum (ER). We enlighten the ER-associated degradation pathway in the context of misfolded, misassembled or tightly regulated ABC transporters with a closer view on the cystic fibrosis transmembrane conductance regulator (CFTR) and the transporter associated with antigen processing (TAP), which plays an essential role in the adaptive immunity. Three rather different scenarios affecting the stability and degradation of ABC transporters are discussed: (1) misfolded domains caused by a lack of proper intra- and intermolecular contacts within the ABC transporters, (2) deficient assembly with auxiliary factors, and (3) arrest and accumulation of an intermediate or ‘dead-end’ state in the transport cycle, which is prone to be recognized by the ER-associated degradation machinery.     

Finding NEMO: nestedness engendered by mutualistic organization in anemonefish and their hosts

The interaction structure of mutualistic relationships, in terms of relative specialization of the partners, is important to understanding their ecology and evolution. Analyses of the mutualistic interaction between anemonefish and their host sea anemones show that the relationship is highly nested in structure, generalist species interacting with one another and specialist species interacting mainly with generalists. This supports the hypothesis that the configuration of mutualistic interactions will tend towards nestedness. In this case, the structure of the interaction is at a much larger scale than previously hypothesized, across more than 180 degrees of longitude and some 60 degrees of latitude, probably owing to the pelagic dispersal capabilities of these species in a marine environment. Additionally, we found weak support for the hypothesis that geographically widespread species should be more generalized in their interactions than species with small ranges. This study extends understanding of the structure of mutualistic relationships into previously unexplored taxonomic and physical realms, and suggests how nestedness analysis can be applied to the conservation of obligate species interactions.     

Muscarinic Agonists Evoke Neurotransmitter Release: Possible Roles for Phosphatidyl Inositol Bisphosphate Breakdown Products in Neuromodulation

Carbachol (CCh), a muscarinic agonist that elicits the formation of inositol trisphosphate (IP3) and diacylglycerol (DG), induces a calcium-dependent [3H]norepinephrine ([3H]NE) release [IC50 = (2.7 +/- 0.5) X 10(-4) M] in rat brain slices. Similarly, other muscarinic agonists evoke [3H]NE release which is specifically inhibited by muscarinic antagonists such as 3-quinuclidinyl benzilate, atropine, and N-methyl-4-piperidyl benzilate. The atropine-sensitive evoked release is effectively inhibited by neomycin (IC50 = 50 microM), a phospholipase C inhibitor that interferes with IP3-dependent cellular processes. In addition, polymyxin B, a rather selective inhibitor of protein kinase C (PK-C), abolishes the agonist-mediated release with a half-maximal effective concentration of 0.53 microM (750 ng/ml). These results have a significant implication for the mechanism by which agonists generating IP3 and DG act as inducers of neurotransmitter release in the CNS. However, since both neomycin and polymyxin B act also as N-calcium-channel blockers, other possible mechanisms are discussed. The CCh-induced release suggests that in the CNS an agonist-receptor interaction leads to a calcium-dependent neurotransmitter release, most likely via promoting the IP3/DG as second messengers followed by activation of PK-C.     

The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue

Introduction  

Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients share many similarities with transformed cancer cells, including spontaneous production of matrix metalloproteinases (MMPs). Altered or chronic activation of proto-oncogenic Ras family GTPases is thought to contribute to inflammation and joint destruction in RA, and abrogation of Ras family signaling is therapeutic in animal models of RA. Recently, expression and post-translational modification of Ras guanine nucleotide releasing factor 1 (RasGRF1) was found to contribute to spontaneous MMP production in melanoma cancer cells. Here, we examine the potential relationship between RasGRF1 expression and MMP production in RA, reactive arthritis, and inflammatory osteoarthritis synovial tissue and FLS.