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991.
Teng‐Kuei Hsu Rhonald C. Lua Angela Dawn Wilkins Olivier Lichtarge 《Protein science : a publication of the Protein Society》2014,23(12):1650-1666
Genome‐wide association studies (GWAS) and whole‐exome sequencing (WES) generate massive amounts of genomic variant information, and a major challenge is to identify which variations drive disease or contribute to phenotypic traits. Because the majority of known disease‐causing mutations are exonic non‐synonymous single nucleotide variations (nsSNVs), most studies focus on whether these nsSNVs affect protein function. Computational studies show that the impact of nsSNVs on protein function reflects sequence homology and structural information and predict the impact through statistical methods, machine learning techniques, or models of protein evolution. Here, we review impact prediction methods and discuss their underlying principles, their advantages and limitations, and how they compare to and complement one another. Finally, we present current applications and future directions for these methods in biological research and medical genetics. 相似文献
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The interaction between arsanilazotyrosine-248 carboxypeptidase A ([(Azo-CPD)Zn]) and excess zinc ions has been studied by stopped-flow and spectrophotometric methods at pH 8.2 and 7.7, I = 0.5 M (NaCl), and 25 degrees C. When excess zinc ions bind to arsanilazotyrosine-248 carboxypeptidase A, the characteristic red color, which arises from the intramolecular complex of the arsanilazotyrosine-248 residue with the active site zinc of the enzyme, changes to yellow with the inhibition of peptidase activity of the enzyme. Excess zinc ions have two binding sites for arsanilazotyrosine-248 carboxypeptidase A, and the binding constants of the first site (3.9 X 10(5) M-1 at pH 8.2; 7.1 X 10(4) M-1 at pH 7.7) are much larger than those of the second site (1.8 X 10(3) M-1 at pH 8.2; 7 X 10(2) M-1 at pH 7.7). The binding of excess zinc ions to the first site is completely correlated with the inhibition of the enzyme peptidase activity and the color change of the enzyme. The results can be understood in terms of zinc ions reacting with only one of three conformational states of arsanilazotyrosine-248 carboxypeptidase A [Harrison, L. W., Auld, D. S., & Vallee, B. L. (1975) Proc. Natl. Acad. Sci. U.S.A. 72, 4356].(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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J L Kinsella J Wehrle N Wilkins B Sacktor 《The Journal of biological chemistry》1987,262(15):7092-7097
The inactivation of rat renal brush border membrane Na+-H+ exchange by the covalent carboxylate reagent N,N'-dicyclohexylcarbodiimide (DCCD) was studied by measuring 1 mM Na+ influx in the presence of a pH gradient (pHi = 5.5; pHo = 7.5) and H+ influx in the presence of a Na+ or Li+ gradient ([Na+]i = 150 mM; [Na+]o = 1.5 mM). In the presence of DCCD, the rate of Na+ uptake decreased exponentially with time and transport inhibition was irreversible. At all DCCD concentrations the loss of activity was described by a single exponential, consistent with one critical DCCD-reactive residue within the Na+-H+ exchanger. Among several carbodiimides the most hydrophobic carbodiimide, DCCD, was also the most effective inhibitor of Na+-H+ exchange. With 40 nmol of DCCD/mg of protein, at 20 degrees C for 30 min, 75% of the amiloride-sensitive 1 mM Na+ uptake was inhibited. Neither the equilibrium Na+ content nor the amiloride-insensitive Na+ uptake was significantly altered by the treatment. The Na+-dependent H+ flux, measured by the change in acridine orange absorbance, was also decreased 80% by the same DCCD treatment. If 150 mM NaCl, 150 mM LiCl, or 1 mM amiloride was present during incubation of the brush border membranes with 40 nmol of DCCD/mg of protein, then Li+-dependent H+ flux was protected 50, 100, or 100%, respectively, compared to membranes treated with DCCD in the absence of Na+-H+ exchanger substrates. The combination of DCCD and an exogenous nucleophile, e.g. ethylenediamine and glycine methyl ester, increased Na+-dependent H+ flux in the presence of 80 nmol of DCCD/mg of protein, compared to the transport after DCCD treatment alone. These findings suggest that the Na+-H+ exchanger contains a single carboxylate residue in a hydrophobic region of the protein, and the carboxylate and/or a nearby endogenous nucleophilic group is critical for exchange activity. 相似文献
997.
Stuart B. Price Carol J. Phelps Tracy D. Wilkins Dr. John L. Johnson 《Current microbiology》1987,16(1):55-60
A portion of the toxin A gene ofClostridium difficile was cloned into pBR322 withEscherichia coli Chi 1776 as the host. Five identical clones, each containing a 4.7-kbPstI restriction endonuclease fragment and producing toxin A antigens, were detected with affinity-purified, monospecific antibodies against toxin A. Digestion of the cloned DNA withPstI revealed as internal restriction site that resulted in two fragments (2.1 and 2.6 kb in size). Probe DNA from either of these fragments hybridized with DNA in the 4.7 kb region ofPstI-digested, high-molecular-weight DNA from the sourceC. difficile strain, indicating that the internalPstI site is protected. The probe DNA also hybridized with restriction-digested DNA from five additional toxigenic strains, but it did not hybridize with DNA from four nontoxigenic strains. In addition, a DNA fragment from a toxigenic strain ofClostridium sordellii, whose toxin cross-reacts with antibody toC. difficile toxin A, hybridized with the clonedC. difficile DNA. Unlike native toxin A, the cell lysate from the recombinant clone was not cytotoxic to Chinese hamster ovary cells or enterotoxic in hamsters. It did agglutinate rabbit red blood cells, a characteristic of toxin A. The cell lysate also exhibited a line of partial identity when compared with purified toxin A in Ouchterlony assays, and it reacted with monoclonal antibody to toxin A in an enzyme-linked immunosorbent assay. The cloned DNA appears to code for a nontoxic binding portion of toxin A, which is responsible for binding to galactose-1-3-galactose-1-4-N-acetylglucosamine.A preliminary report of this work has been presented by S.B. Price and J.L. Johnson, Abstracts of the Annual Meeting of the American Society for Microbiology, 1986:67. 相似文献
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Cinemicrographic Study of the Development of Subsurface Colonies of Staphylococcus aureus in Soft Agar 下载免费PDF全文
Cinemicrographic studies revealed that the development of elongated subsurface colonies of Staphylococcus aureus in soft agar (<0.2% agar) originated with a colony-forming unit of about 10 to 20 cells. It was then observed that small clusters of 3 to 12 cells broke off from the main colony unit and drifted away under the combined influence of gravity and Brownian motion. Once the downward or slightly sideward motion of the small clusters ceased, the clusters would continue to increase in size; at the same time, additional small clusters broke off, and the cycle was repeated until the entire colony was formed. Displacement and velocity measurements were made on the drifting small clusters. When compared with the dimensional growth rate and geometry of the subsurface colony, these showed that a correlation existed between the movement and velocity of the small clusters and the subsequent colony development. A relationship between the role of gravity reported in these results and the development of spherical colonies after rotation on a clinostat is suggested. 相似文献