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771.
Sustained secretion of anti‐tumor necrosis factor α monoclonal antibody from ex vivo genetically engineered dermal tissue demonstrates therapeutic activity in mouse model of rheumatoid arthritis
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772.
We present a new method for detecting coevolving sites in molecules. The method relies on a set of aligned sequences (nucleic acid or protein) and uses Markov models of evolution to map the substitutions that occurred at each site onto the branches of the underlying phylogenetic tree. This mapping takes into account the uncertainty over ancestral states and among-site rate variation. We then build, for each site, a "substitution vector" containing the posterior estimates of the number of substitutions in each branch. The amount of coevolution for a pair of sites is then measured as the Pearson correlation coefficient between the two corresponding substitution vectors and compared to the expectation under the null hypothesis of independence. We applied the method to a 79-species bacterial ribosomal RNA data set, for which extensive structural characterization has been done over the last 30 years. More than 95% of the intramolecular predicted pairs of sites correspond to known interacting site pairs. 相似文献
773.
The HSSP (Homology-Derived Secondary Structure of Proteins) database provides multiple sequence alignments (MSAs) for proteins of known three-dimensional (3D) structure in the Protein Data Bank (PDB). The database also contains an estimate of the degree of evolutionary conservation at each amino acid position. This estimate, which is based on the relative entropy, correlates with the functional importance of the position; evolutionarily conserved positions (i.e., positions with limited variability and low entropy) are occasionally important to maintain the 3D structure and biological function(s) of the protein. We recently developed the Rate4Site algorithm for scoring amino acid conservation based on their calculated evolutionary rate. This algorithm takes into account the phylogenetic relationships between the homologs and the stochastic nature of the evolutionary process. Here we present the ConSurf-HSSP database of Rate4Site estimates of the evolutionary rates of the amino acid positions, calculated using HSSP's MSAs. The database provides precalculated evolutionary rates for nearly all of the PDB. These rates are projected, using a color code, onto the protein structure, and can be viewed online using the ConSurf server interface. To exemplify the database, we analyzed in detail the conservation pattern obtained for pyruvate kinase and compared the results with those observed using the relative entropy scores of the HSSP database. It is reassuring to know that the main functional region of the enzyme is detectable using both conservation scores. Interestingly, the ConSurf-HSSP calculations mapped additional functionally important regions, which are moderately conserved and were overlooked by the original HSSP estimate. The ConSurf-HSSP database is available online (http://consurf-hssp.tau.ac.il). 相似文献
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776.
Laboratory soil bioassays were performed at economic field rates for in-furrow (3.85 x 10(6)spores/g dry soil) and broadcast (3.85 x 10(5)spores/g dry soil) applications with three isolates of Metarhizium anisopliae (F52, ATCC62176, and ARSEF5520) and one isolate of Beauveria bassiana (GHA). All isolates tested were infective to second instar Delia radicum (L.). The conditionally registered M. anisopliae isolate (F52) performed best killing an average of 85 and 72% of D. radicum larvae at the high and low concentration, respectively. The mean LC50 and LC95 of F52 against second instar D. radicum was 2.7 x 10(6) and 1.8 x 10(8)spores/g dry soil, respectively. The use of F52 in an integrated management program is discussed. 相似文献
777.
Yudowski GA Bar Shimon M Tal DM González-Lebrero RM Rossi RC Garrahan PJ Beaugé LA Karlish SJ 《Biochemistry》2003,42(34):10212-10222
A family of aryl isothiouronium derivatives was designed as probes for cation binding sites of Na(+),K(+)-ATPase. Previous work showed that 1-bromo-2,4,6-tris(methylisothiouronium)benzene (Br-TITU) acts as a competitive blocker of Na(+) or K(+) occlusion. In addition to a high-affinity cytoplasmic site (K(D) < 1 microM), a low-affinity site (K(D) approximately 10 microM) was detected, presumably extracellular. Here we describe properties of Br-TITU as a blocker at the extracellular surface. In human red blood cells Br-TITU inhibits ouabain-sensitive Na(+) transport (K(D) approximately 30 microM) in a manner antagonistic with respect to extracellular Na(+). In addition, Br-TITU impairs K(+)-stimulated dephosphorylation and Rb(+) occlusion from phosphorylated enzyme of renal Na(+),K(+)-ATPase, consistent with binding to an extracellular site. Incubation of renal Na(+),K(+)-ATPase with Br-TITU at pH 9 irreversibly inactivates Na(+),K(+)-ATPase activity and Rb(+) occlusion. Rb(+) or Na(+) ions protect. Preincubation of Br-TITU with red cells in a K(+)-free medium at pH 9 irreversibly inactivates ouabain-sensitive (22)Na(+) efflux, showing that inactivation occurs at an extracellular site. K(+), Cs(+), and Li(+) ions protect against this effect, but the apparent affinity for K(+), Cs(+), or Li(+) is similar (K(D) approximately 5 mM) despite their different affinities for external activation of the Na(+) pump. Br-TITU quenches tryptophan fluorescence of renal Na(+),K(+)-ATPase or of digested "19 kDa membranes". After incubation at pH 9 irreversible loss of tryptophan fluorescence is observed and Rb(+) or Na(+) ions protect. The Br-TITU appears to interact strongly with tryptophan residue(s) within the lipid or at the extracellular membrane-water interface and interfere with cation occlusion and Na(+),K(+)-ATPase activity. 相似文献
778.
779.
The ratio of radical to conservative amino acid replacements is frequently used to infer positive Darwinian selection. This method is based on the assumption that radical replacements are more likely than conservative replacements to improve the function of a protein. Therefore, if positive selection plays a major role in the evolution of a protein, one would expect the radical-conservative ratio to exceed the expectation under neutrality. Here, we investigate the possibility that factors unrelated to selection, i.e., transition-transversion ratio, codon usage, genetic code, and amino acid composition, influence the radical-conservative replacement ratio. All factors that have been studied were found to affect the radical-conservative replacement ratio. In particular, amino acid composition and transition-transversion ratio are shown to have the most profound effects. Because none of the studied factors had anything to do with selection (positive or otherwise) and also because all of them (singly or in combination) affected a measure that was supposed to be indicative of positive selection, we conclude that selectional inferences based on radical-conservative replacement ratios should be treated with suspicion. 相似文献
780.
Bruck I Yuzhakov A Yurieva O Jeruzalmi D Skangalis M Kuriyan J O'Donnell M 《The Journal of biological chemistry》2002,277(19):17334-17348
This report takes a proteomic/genomic approach to characterize the DNA polymerase III replication apparatus of the extreme thermophile, Aquifex aeolicus. Genes (dnaX, holA, and holB) encoding the subunits required for clamp loading activity (tau, delta, and delta') were identified. The dnaX gene produces only the full-length product, tau, and therefore differs from Escherichia coli dnaX that produces two proteins (gamma and tau). Nonetheless, the A. aeolicus proteins form a taudeltadelta' complex. The dnaN gene encoding the beta clamp was identified, and the taudeltadelta' complex is active in loading beta onto DNA. A. aeolicus contains one dnaE homologue, encoding the alpha subunit of DNA polymerase III. Like E. coli, A. aeolicus alpha and tau interact, although the interaction is not as tight as the alpha-tau contact in E. coli. In addition, the A. aeolicus homologue to dnaQ, encoding the epsilon proofreading 3'-5'-exonuclease, interacts with alpha but does not form a stable alpha.epsilon complex, suggesting a need for a brace or bridging protein to tightly couple the polymerase and exonuclease in this system. Despite these differences to the E. coli system, the A. aeolicus proteins function to yield a robust replicase that retains significant activity at 90 degrees C. Similarities and differences between the A. aeolicus and E. coli pol III systems are discussed, as is application of thermostable pol III to biotechnology. 相似文献