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131.
LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons 总被引:3,自引:0,他引:3
Barnes AP Lilley BN Pan YA Plummer LJ Powell AW Raines AN Sanes JR Polleux F 《Cell》2007,129(3):549-563
The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. We show here that the serine/threonine kinase LKB1, previously implicated in the establishment of epithelial polarity and control of cell growth, is required for axon specification during neuronal polarization in the mammalian cerebral cortex. LKB1 polarizing activity requires its association with the pseudokinase Stradalpha and phosphorylation by kinases such as PKA and p90RSK, which transduce neurite outgrowth-promoting cues. Once activated, LKB1 phosphorylates and thereby activates SAD-A and SAD-B kinases, which are also required for neuronal polarization in the cerebral cortex. SAD kinases, in turn, phosphorylate effectors such as microtubule-associated proteins that implement polarization. Thus, we provide evidence in vivo and in vitro for a multikinase pathway that links extracellular signals to the intracellular machinery required for axon specification. 相似文献
132.
The evolutionary rate of proteins involved in obligate protein-protein interactions is slower and the degree of coevolution higher than that for nonobligate protein-protein interactions. The coevolution of the proteins involved in certain nonobligate interactions is, however, essential to cell survival. To gain insight into the coevolution of one such nonobligate protein pair, the cytosolic ribonuclease inhibitor (RI) proteins and secretory pancreatic-type ribonucleases from cow (Bos taurus) and human (Homo sapiens) were produced in Escherichia coli and purified, and their physicochemical properties were analyzed. The two intraspecies complexes were found to be extremely tight (bovine Kd = 0.69 fM; human Kd = 0.34 fM). Human RI binds to its cognate ribonuclease (RNase 1) with 100-fold greater affinity than to the bovine homologue (RNase A). In contrast, bovine RI binds to RNase 1 and RNase A with nearly equal affinity. This broader specificity is consistent with there being more pancreatic-type ribonucleases in cows (20) than humans (13). Human RI (32 cysteine residues) also has 4-fold less resistance to oxidation by hydrogen peroxide than does bovine RI (29 cysteine residues). This decreased oxidative stability of human RI, which is caused largely by Cys74, implies a larger role for human RI as an antioxidant. The conformational and oxidative stabilities of both RIs increase upon complex formation with ribonucleases. Thus, RI has evolved to maintain its inhibition of invading ribonucleases, even when confronted with extreme environmental stress. That role appears to take precedence over its role in mediating oxidative damage. 相似文献
133.
Cells tightly regulate their contents. Still, nonspecific Coulombic interactions between cationic molecules and anionic membrane components can lead to adventitious endocytosis. Here, we characterize this process in a natural system. To do so, we create variants of human pancreatic ribonuclease (RNase 1) that differ in net molecular charge. By conjugating a small-molecule latent fluorophore to these variants and using flow cytometry, we are able to determine the kinetic mechanism for RNase 1 internalization into live human cells. We find that internalization increases with solution concentration and is not saturable. Internalization also increases with time to a steady-state level, which varies linearly with molecular charge. In contrast, the rate constant for internalization (t1/2 = 2 h) is independent of charge. We conclude that internalization involves an extracellular equilibrium complex between the cationic proteins and abundant anionic cell-surface molecules, followed by rate-limiting internalization. The enhanced internalization of more cationic variants of RNase 1 is, however, countered by their increased affinity for the cytosolic ribonuclease inhibitor protein, which is anionic. Thus, Coulombic forces mediate extracellular and intracellular equilibria in a dichotomous manner that both endangers cells and defends them from the potentially lethal enzymatic activity of ribonucleases. 相似文献
134.
With its wide distribution in soft and hard connective tissues, collagen is the most abundant of animal proteins. In vitro, natural collagen can be formed into highly organized, three‐dimensional scaffolds that are intrinsically biocompatible, biodegradable, nontoxic upon exogenous application, and endowed with high tensile strength. These attributes make collagen the material of choice for wound healing and tissue engineering applications. In this article, we review the structure and molecular interactions of collagen in vivo; the recent use of natural collagen in sponges, injectables, films and membranes, dressings, and skin grafts; and the on‐going development of synthetic collagen mimetic peptides as pylons to anchor cytoactive agents in wound beds. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 821–833, 2014. 相似文献
135.
Chelcie H. Eller Jo E. Lomax Ronald T. Raines 《The Journal of biological chemistry》2014,289(38):25996-26006
Mounting evidence suggests that human pancreatic ribonuclease (RNase 1) plays important roles in vivo, ranging from regulating blood clotting and inflammation to directly counteracting tumorigenic cells. Understanding these putative roles has been pursued with continual comparisons of human RNase 1 to bovine RNase A, an enzyme that appears to function primarily in the ruminant gut. Our results imply a different physiology for human RNase 1. We demonstrate distinct functional differences between human RNase 1 and bovine RNase A. Moreover, we characterize another RNase 1 homolog, bovine brain ribonuclease, and find pronounced similarities between that enzyme and human RNase 1. We report that human RNase 1 and bovine brain ribonuclease share high catalytic activity against double-stranded RNA substrates, a rare quality among ribonucleases. Both human RNase 1 and bovine brain RNase are readily endocytosed by mammalian cells, aided by tight interactions with cell surface glycans. Finally, we show that both human RNase 1 and bovine brain RNase are secreted from endothelial cells in a regulated manner, implying a potential role in vascular homeostasis. Our results suggest that brain ribonuclease, not RNase A, is the true bovine homolog of human RNase 1, and provide fundamental insight into the ancestral roles and functional adaptations of RNase 1 in mammals. 相似文献
136.
Lise Musset Stéphane Pelleau Romain Girod Vanessa Ardillon Luisiane Carvalho Isabelle Dusfour Margarete SM Gomes Félix Djossou Eric Legrand 《Memórias do Instituto Oswaldo Cruz》2014,109(5):525-533
In a climate of growing concern that Plasmodium falciparum may be
developing a drug resistance to artemisinin derivatives in the Guiana Shield, this
review details our current knowledge of malaria and control strategy in one part of
the Shield, French Guiana. Local epidemiology, test-treat-track strategy, the state
of parasite drug resistance and vector control measures are summarised. Current
issues in terms of mobile populations and legislative limitations are also
discussed. 相似文献
137.
Kevin K. Desai Craig A. Bingman Chin L. Cheng George N. Phillips Jr. Ronald T. Raines 《RNA (New York, N.Y.)》2014,20(10):1560-1566
RNA 3′-phosphate cyclase (RtcA) catalyzes the ATP-dependent cyclization of a 3′-phosphate to form a 2′,3′-cyclic phosphate at RNA termini. Cyclization proceeds through RtcA–AMP and RNA(3′)pp(5′)A covalent intermediates, which are analogous to intermediates formed during catalysis by the tRNA ligase RtcB. Here we present a crystal structure of Pyrococcus horikoshii RtcA in complex with a 3′-phosphate terminated RNA and adenosine in the AMP-binding pocket. Our data reveal that RtcA recognizes substrate RNA by ensuring that the terminal 3′-phosphate makes a large contribution to RNA binding. Furthermore, the RNA 3′-phosphate is poised for in-line attack on the P–N bond that links the phosphorous atom of AMP to Nε of His307. Thus, we provide the first insights into RNA 3′-phosphate termini recognition and the mechanism of 3′-phosphate activation by an Rtc enzyme. 相似文献
138.
Quantitative analysis of organophosphorus pesticides in freshwater using an optimized firefly luciferase‐based coupled bioluminescent assay
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In this paper, a coupled bioluminescent assay, relying on the coupling of the enzymes acetylcholinesterase, S‐acetyl‐coenzyme A synthetase and firefly luciferase, for the detection and quantitation of organophosphorus pesticides, is presented. Using malathion as a model organophosphorus pesticide, the assay was optimized through statistical experimental design methodology, namely Plackett–Burman and central composite designs. The optimized method requires only 20 μL of sample. The linear range for the assay was 2.5–15 μM of malathion, with limits of detection and quantitation of 1.5 and 5.0 μM, respectively. This simple, fast and robust method allows samples to be analyzed at room temperature and without any pretreatment. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
139.
Robert W. Newberry Gail J. Bartlett Brett VanVeller Derek N. Woolfson Ronald T. Raines 《Protein science : a publication of the Protein Society》2014,23(3):284-288
The folding of proteins is directed by a variety of interactions, including hydrogen bonding, electrostatics, van der Waals' interactions, and the hydrophobic effect. We have argued previously that an n→π* interaction between carbonyl groups be added to this list. In an n→π* interaction, the lone pair (n) of one carbonyl oxygen overlaps with the π* antibonding orbital of another carbonyl group. The tendency of backbone carbonyl groups in proteins to engage in this interaction has consequences for the structures of folded proteins that we unveil herein. First, we employ density functional theory to demonstrate that the n→π* interaction causes the carbonyl carbon to deviate from planarity. Then, we detect this signature of the n→π* interaction in high‐resolution structures of proteins. Finally, we demonstrate through natural population analysis that the n→π* interaction causes polarization of the electron density in carbonyl groups and detect that polarization in the electron density map of cholesterol oxidase, further validating the existence of n→π* interactions. We conclude that the n→π* interaction is operative in folded proteins. 相似文献
140.
Snake venoms are cocktails comprising combinations of different proteins, peptides, enzymes and toxins. Snake toxins have
diverse characteristics having different molecular configuration, structure and mode of action. Many toxins derived from snake
venom have distinct pharmacological activities. Venom from Bungarus fasciatus (commonly known as banded krait) is a species of
elapid snake found on the South East Asia and Indian sub-continent, mainly contains neurotoxins. Beta bungartotoxin is the major
fraction of Bungarus venom and particularly act pre-synaptically by obstructing neurotransmitter release. This toxin in other
snake species functionally forms a heterodimer containing two different subunits (A and B). Dimerization of these two chains is a
pre-requisite for the proper functionality of this protein. However, B. fasciatus bungartotoxin contains only B chain and their
structural orientation in yet to be resolved. Therefore, it is of interest to describe the predicted structure model of the toxin for
functional insights. In this work we analyzed the neurotoxic nature, their alignments, secondary and three dimensional structures,
functions, active sites and stability with the help of different bioinformatical tools. A comprehensive analysis of the predicted model
provides approaching to the functional interpretation of its molecular action. 相似文献