Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced numbers of frictional/scattering centers are essential for tractable hydrodynamic and small-angle scattering data modeling. We present a method for generating medium-resolution models from the atomic coordinates of proteins, basically by using two nonoverlapping spheres of differing radii per residue. The computed rigid-body hydrodynamic parameters of BPTI, RNase A, and lysozyme models were compared with a large database of critically assessed experimental values. Overall, very good results were obtained, but significant discrepancies between X-ray- and NMR-derived models were found. Interestingly, they could be accounted for by properly considering the extent to which highly mobile surface side chains differently affect translational/rotational properties. Models of larger structures, such as fibrinogen fragment D and citrate synthase, also produced consistent results. Foremost among this method's potential applications is the overall conformation and dynamics of modular/multidomain proteins and of supramolecular complexes. The possibility of merging data from high- and low-resolution structures greatly expands its scope.
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PMID:SOMO (SOlution MOdeler) differences between X-Ray- and NMR-derived bead models suggest a role for side chain flexibility in protein hydrodynamics. 1589 63

Partially or completely unfolded polypeptides are highly prone to aggregation due to nonspecific interactions between their exposed hydrophobic surfaces. Extracellular proteins are continuously subjected to stresses conditions, but the existence of extracellular chaperones remains largely unexplored. The results presented here demonstrate that one of the most abundant extracellular proteins, fibrinogen has chaperone-like activity. Fibrinogen can specifically bind to nonnative form of citrate synthase and inhibit its thermal aggregation and inactivation in an ATP-independent manner. Interestingly, fibrinogen maintains thermal-denatured luciferase in a refolding competent state allowing luciferase to be refolded in cooperation with rabbit reticulocyte lysate. Fibrinogen also inhibits fibril formation of yeast prion protein Sup35 (NM). Furthermore, fibrinogen rescues thermal-induced protein aggregation in the plasma of fibrinogen-deficient mice. Our studies demonstrate the chaperone-like activity of fibrinogen, which not only provides new insights into the extracellular chaperone protein system, but also suggests potential diagnostic and therapeutic approaches to fibrinogen-related pathological conditions.
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PMID:Fibrinogen has chaperone-like activity. 1905 6

Human fibrinogen is an important coagulation factor as well as an acute phase protein in the circulatory system. Fibrinogen-420 is distinguished from the conventional alpha chain of fibrinogen-340 by the presence of an additional 236-residue carboxyl terminus globular domain (alpha(E)C). The alpha(E)C domain of human fibrinogen-420 is a stable and early proteolytic cleavage product in the circulation. A genuine physiological function for alpha(E)C has not yet been established. Our study aims to characterize the novel chaperone-like activity of alpha(E)C. alpha(E)C efficiently protects a series of model proteins from thermally induced aggregation. Furthermore, alpha(E)C specifically recognizes the partially denatured form instead of the native form of citrate synthase (CS) and potentially protects it from thermally induced inactivation. The protective effect may result from formation of soluble complexes between alpha(E)C and partially denatured CS as tested by size exclusion column and electron microscope. In addition, alpha(E)C can keep the partially denatured luciferase in a folding competent state and help it refold in cooperation with rabbit reticulocyte lysate (RRL). Furthermore, alpha(E)C can also form complexes with thermally stressed plasma proteins. Our findings reveal the novel function of alpha(E)C as a chaperone-like protein, which not only provides new insights into the extracellular chaperone system but also has implications on the physiological and pathological relevance of fibrinogen.
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PMID:Alpha(E)C, the C-terminal extension of fibrinogen, has chaperone-like activity. 1928 87

Clusterin (CLU) is a potent extracellular chaperone that inhibits protein aggregation and precipitation otherwise caused by physical or chemical stresses (e.g. heat, reduction). This action involves CLU forming soluble high molecular weight (HMW) complexes with the client protein. Other than their unquantified large size, the physical characteristics of these complexes were previously unknown. In this study, HMW CLU-citrate synthase (CS), HMW CLU-fibrinogen (FGN), and HMW CLU-glutathione S-transferase (GST) complexes were generated in vitro, and their structures studied using size exclusion chromatography (SEC), ELISA, SDS-PAGE, dynamic light scattering (DLS), bisANS fluorescence, and circular dichroism spectrophotometry (CD). Densitometry of Coomassie Blue-stained SDS-PAGE gels indicated that all three HMW CLU-client protein complexes had an approximate mass ratio of 1:2 (CLU:client protein). SEC indicated that all three clients formed complexes with CLU>or=4x10(7) Da; however, DLS estimated HMW CLU-FGN to have a diameter of 108.57+/-18.09 nm, while HMW CLU-CS and HMW CLU-GST were smaller with estimated diameters of 51.06+/-6.87 nm and 52.61+/-7.71 nm, respectively. Measurements of bisANS fluorescence suggest that the chaperone action of CLU involves preventing the exposure to aqueous solvent of hydrophobic regions that are normally exposed by the client protein during heat-induced unfolding. CD analysis indicated that, depending on the individual client protein, CLU may interact with a variety of intermediates on protein unfolding pathways with different amounts of native secondary structure. In vivo, soluble complexes like those studied here are likely to serve as vehicles to dispose of otherwise dangerous aggregation-prone misfolded extracellular proteins.
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PMID:Structural characterization of clusterin-chaperone client protein complexes. 1953 39

Decompression sickness (DCS) is a complex and poorly understood systemic disease with wide interindividual resistance variability. We selectively bred rats with a threefold greater resistance to DCS than standard ones. To investigate possible physiological mechanisms underlying the resistance to DCS, including sex-related differences in these mechanisms, 15 males and 15 females resistant to DCS were compared with aged-matched standard Wistar males (n = 15) and females (n = 15). None of these individuals had been previously exposed to hyperbaric treatment. Comparison of the allelic frequencies of single nucleotide polymorphisms (SNPs) showed a difference of one SNP located on the X chromosome. Compared with nonresistant rats, the neutrophil-to-lymphocyte ratio and the plasmatic activity of coagulation factor X were significantly higher in DCS-resistant individuals regardless of their sex. The maximal relaxation elicited by sodium nitroprusside was lower in DCS-resistant individuals regardless of their sex. Males but not females resistant to DCS exhibited higher neutrophil and lymphocyte counts and higher prothrombin time but lower mitochondrial basal O2 consumption and citrate synthase activity. Principal components analysis showed that two principal components discriminate the DCS-resistant males but not females from the nonresistant ones. These components were loaded with activated partial thromboplastin time, monocyte-to-lymphocyte ratio, prothrombin time, factor X, and fibrinogen for PC1 and red blood cells count and neutrophils count for PC2. In conclusion, the mechanisms that drive the resistance to DCS appear different between males and females; lower coagulation tendency and enhanced inflammatory response to decompression stress might be key for resistance in males. The involvement of these physiological adaptations in resistance to DCS must now be confirmed.NEW & NOTEWORTHY By selective breeding of individuals resistant to decompression sickness (DCS) we previously obtained a rat model of inherited resistance to this pathology. Comparison of these individuals with nonresistant animals revealed differences in leukocyte counts, coagulation, and mitochondrial and vascular functions, but not resistance to oxidative stress. This study also reveals sex-related differences in the physiological changes associated with DCS resistance. A principal components analysis of our data allowed us to discriminate DCS-resistant males from standard ones, but not females. These differences represent possible mechanisms driving resistance to DCS. Although still far from the diver, this opens a pathway to future adaptation of personalized decompression procedures for "DCS-prone" individuals.
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PMID:Physiological characteristics associated with increased resistance to decompression sickness in male and female rats. 3270 69