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91.
Modification of actin at Cys (374) with tetramethylrhodamine maleimide (TMR-actin) has been used for visualization of actin filaments and to produce high-resolution crystal structures of actin. We show that TMR-actin exhibits a 21% decrease in absorbance at 557 nm upon thermal unfolding, likely due to the movement of TMR to a more hydrophobic environment upon rapid unfolding and protein aggregation. We took advantage of this property to test models of actin protein unfolding. A transition temperature ( T m) of 60.2 +/- 0.2 degrees C for Ca (2+).ATP.TMR-actin was determined using A 557 and agreed with our own determinations employing different techniques and previous work with unlabeled actin. Our data show that the dependence of TMR-actin thermal stability on the bound nucleotide and cations follows a trend of Ca (2+).ATP > Mg (2+).ATP > Ca (2+).ADP > Mg (2+).ADP. The activation energies and frequency factors for the thermal unfolding of TMR-actin determined with two methods were in good agreement with those previously determined for unlabeled actin. We observed a biphasic trend in the T m of TMR-actin with increasing nucleotide concentrations, supporting a two-pathway model for actin protein unfolding where one pathway dominates at different concentrations of nucleotide. Additionally, TMR-actin bound by DNase I or gelsolin segment-1 exhibited elevated transition temperatures. 相似文献
92.
Adeera Levin Brenda Hemmelgarn Bruce Culleton Sheldon Tobe Philip McFarlane Marcel Ruzicka Kevin Burns Braden Manns Colin White Francoise Madore Louise Moist Scott Klarenbach Brendan Barrett Robert Foley Kailash Jindal Peter Senior Neesh Pannu Sabin Shurraw Ayub Akbari Adam Cohn Martina Reslerova Vinay Deved David Mendelssohn Gihad Nesrallah Joanne Kappel Marcello Tonelli for the Canadian Society of Nephrology 《CMAJ》2008,179(11):1154-1162
93.
Evdokimov AG Mekel M Hutchings K Narasimhan L Holler T McGrath T Beattie B Fauman E Yan C Heaslet H Walter R Finzel B Ohren J McConnell P Braden T Sun F Spessard C Banotai C Al-Kassim L Ma W Wengender P Kole D Garceau N Toogood P Liu J 《Journal of structural biology》2008,162(1):152-169
In this article, we describe for the first time the high-resolution crystal structure of a phenylalanine tRNA synthetase from the pathogenic bacterium Staphylococcus haemolyticus. We demonstrate the subtle yet important structural differences between this enzyme and the previously described Thermus thermophilus ortholog. We also explain the structure-activity relationship of several recently reported inhibitors. The native enzyme crystals were of poor quality--they only diffracted X-rays to 3-5A resolution. Therefore, we have executed a rational surface mutagenesis strategy that has yielded crystals of this 2300-amino acid multidomain protein, diffracting to 2A or better. This methodology is discussed and contrasted with the more traditional domain truncation approach. 相似文献
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95.
Double-stranded RNA binding domain (dsRBD) containing proteins are critical components of the microRNA (miRNA) pathway, with key roles in small RNA biogenesis, modification, and regulation. DiGeorge Critical Region 8 (DGCR8) is a 773 amino acid, dsRBD-containing protein that was originally identified in humans as a protein encoded in the region of chromosome 22 that is deleted in patients with DiGeorge syndrome. Now, it is realized that DGCR8 complements the nuclear RNase III Drosha to initiate miRNA biogenesis by promoting efficient recognition and cleavage of primary miRNAs (pri-miRNA). A pair of C-terminal tandem dsRBDs separated by a flexible linker are required for pri-miRNA substrate binding and recognition. The crystal structure of the DGCR8 core region comprising residues 493–720 revealed that each dsRBD adopts the canonical αβββα fold. However, several residues located in important flexible regions including the β1-β2-loop implicated in canonical dsRNA recognition are absent in the crystal structure and no RNA-bound structure of DGCR8 has been reported. Here we report the 1HN, 13C, and 15N backbone resonance assignments of the 24 kDa, 214 amino acid human DGCR8core (residues 493–706) by heteronuclear NMR spectroscopy. Our assignments lay the foundation for a detailed solution state characterization of the dynamical and RNA-binding properties of this protein in solution. 相似文献
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Chung JY Davis JA Price BD Staley DM Wagner MV Warner SL Bearss DJ Hansen MD 《Experimental cell research》2011,(3):307-318
HGF signaling induces epithelial cells to disassemble cadherin-based adhesion and increase cell motility and invasion, a process termed epithelial–mesenchymal transition (EMT). EMT plays a major role in cancer metastasis, allowing individual cells to detach from the primary tumor, invade local tissue, and colonize distant tissues with new tumors. While invasion of vascular and lymphatic networks is the predominant route of metastasis, nerves also can act as networks for dissemination of cancer cell to distant sites in a process termed perineual invasion (PNI). Signaling between nerves and invasive cancer cells remains poorly understood, as does cellular decision making that selects the specific route of invasion. Here we examine how HGF signaling contributes to PNI using reductionist culture model systems. We find that TGFβ, produced by PC12 cells, enhances scattering in response to HGF stimulation, increasing both cell–cell junction disassembly and cell migration. Further, gradients of TGFβ induce migratory mesenchymal cells to undergo chemotaxis towards the source of TGFβ. Interestingly, VEGF suppresses TGFβ-induced enhancement of scattering. These results have broad implications for how combinatorial growth factor signaling contributes to cancer metastasis, suggesting that VEGF and TGFβ might modulate HGF signaling to influence route selection during cancer progression. 相似文献
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99.
Acierno JP Braden BC Klinke S Goldbaum FA Cauerhff A 《Journal of molecular biology》2007,374(1):130-146
The somatic mutations accumulated in variable and framework regions of antibodies produce structural changes that increase the affinity towards the antigen. This implies conformational and non covalent bonding changes at the paratope, as well as possible quaternary structure changes and rearrangements at the VH-VL interface. The consequences of the affinity maturation on the stability of the Fv domain were studied in a system composed of two closely related antibodies, F10.6.6 and D44.1, which recognize the same hen egg-white lysozyme (HEL) epitope. The mAb F10.6.6 has an affinity constant 700 times higher than D44.1, due to a higher surface complementarity to HEL. The structure of the free form of the Fab F10.6.6 presented here allows a comparative study of the conformational changes produced upon binding to antigen. By means of structural comparison, kinetics and thermodynamics of binding and stability studies on Fab and Fv fragments of both antibodies, we have determined that the affinity maturation process of anti-protein antibodies affects the shape of the combining site and the secondary structure content of the variable domain, stabilizes the VH-VL interaction, and consequently produces an increase of the Fv domain stability, improving the binding to antigen. 相似文献
100.