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PubMed1976

The mechanism of the aminoacylation of transfer ribonucleic acid: enzyme-product dissociation is not rate limiting.

It has been proposed that the rate-limiting step in the synthesis of aminoacyl-tRNA is the rate at which the product dissociates from the enzyme. The experimental evidence supporting this hypothesis comes from work at low pH and low temperature (although the reaction has been argued to have the same mechanism under physiological conditions). We have reexamined the binding assay by which M. Yarus and P. Berg (1969) (J. Mol. Biol. 42, 171-189) measured the kd for dissociation of Enz-(Ile-tRNA). We find that when overall reaction and dissociation are measured under identical conditions the two rates are not the same. Moreover, while an increase in ionic strength greatly stimulates dissociation, the same increased ionic strength slows aminoacylation. Spermine accelerates overall aminoacylation without affecting dissociation. Because any change in a rate-limiting step must, by definition, cause a parallel change in the overall reaction, these observations prove that under these conditions the synthesis of Ile-tRNA is not limited by the rate of dissociation of Enz-(Ile-tRNA). Entirely similar observations were made for the dissociation of Enz-(Val-tRNA) and the overall synthesis of Val-tRNA at 0 degrees C, PH 5.0. In addition, valine enzyme isolated by nitrocellulose filtration during the course of an aminoacylation was shown not to be saturated with recently synthesized Val-tRNA. The enzyme was in equilibrium with uncharged substrate tRNA and with product Val-tRNA. E. W. Eldred and P. R. Schimmel ((1972) Biochemistry 11, 17-23) report that the formation of Ile-tRNA proceeds at two rates: (a) k = 2 X 10(-2)S(-1) until the enzyme is saturated with the first mole of product, and (b) k = 2 X 10(-3)S(-1) for subsequent cycles. We did not observe this behavior at any pH or temperature with four different amino acid:tRNA ligases. Because aminoacylation proceeds more rapidly than "dissociation" under some conditions, we believe that the binding assay measures not only enzyme-product dissociation but also other slower reactions such as aggregation or disaggregation of Enz-(AA-tRNA). In conjunction with recent studies from other laboratories, this work makes it unlikely that enzyme-product dissociation is the rate-limiting step in the synthesis of aminoacyl-tRNA either at low temperature and pH or under more nearly physiological conditions. From the effect of salt, it would appear that the rate of aminoacylation of tRNA is largely limited by the rate or extent of formation of Enz-(tRNA) (Loftfield, R. B., and Eigner, E. A. (1967), J. Biol. Chem. 242, 5355-5359). Using the binding assay of M. Yarus ((1972) Biochemistry 11, 2050-2060), we find the Kass for Enz-(Ile-tRNA) varies linearly with the Debye-Hückel function at ionic strengths of 0.1-0.4 from 10(8) to 10(6).

Amino Acyl-tRNA Synthetases↗
PubMed2005

Cl-loss and H-loss dissociations in low-lying electronic states of the CH3Cl+ ion studied using multiconfiguration second-order perturbation theory.

To examine the experimentally suggested scheme of the pathways for Cl- and H-loss dissociations of the CH(3)Cl(+) ion in the X(2)E (1(2)A', 1(2)A' '), A(2)A(1) (2(2)A'), and B(2)E (3(2)A', 2(2)A") states, the complete active space-self-consistent field (CASSCF) and multiconfiguration second-order perturbation theory (CASPT2) calculations with an atomic natural orbital (ANO) basis were performed for the 1(2)A' (X(2)A'), 1(2)A", 2(2)A', and 2(2)A'" states. The potential energy curves describing dissociation from the four C(s) states were obtained on the basis of the CASSCF partial geometry optimization calculations at fixed C-Cl or C-H distance values, followed by the CASPT2 energy calculations. The electronic states of the CH3(+) and CH(2)Cl(+) ions produced by Cl-loss and H-loss dissociation, respectively, were carefully determined. Our calculations confirm the following experimental facts: Cl-loss dissociation occurs from the 1(2)A' (X(2)A'), 1(2)A", and 2(2)A' states (all leading to CH3(+) (X(1)A(1)') + Cl), and H-loss dissociation does not occur from 2(2)A'. The calculations indicate that H-loss dissociation occurs from the 1(2)A' and 1(2)A' ' states (leading to CH(2)Cl(+) (X(1)A(1)) + H and CH(2)Cl(+) (1(3)A") + H, respectively). The calculations also indicate that H-loss dissociation occurs (with a barrier) from the 2(2)A" state (leading to CH(2)Cl(+) (1(1)A") + H), supporting the observation of direct dissociation from the B state to CH(2)Cl(+) and that Cl-loss dissociation occurs from the 2(2)A" state (leading to CH3(+) (1(3)A") + Cl), not supporting the previously proposed Cl-loss dissociation of the B state via internal conversion of B to A. The predicted appearance potential values for CH3(+) (X(1)A(1)') and CH(2)Cl(+) (X(1)A(1)) are in good agreement with the experimental values.

Journal Article↗
PubMed1992

Beta-adrenergic-receptor-mediated dissociation and membrane release of the Gs protein in S49 lymphoma-cell membranes. Dependence on Mg2+ and GTP.

We reported [Ransnäs, Svoboda, Jasper & Insel (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 7900-7903] that in intact S49 lymphoma cells the beta-adrenergic-receptor agonist isoprenaline dissociates the stimulatory guanine-nucleotide-binding protein, Gs, into its alpha s and beta gamma subunits, leading to redistribution of alpha s from plasma membranes to the cytoplasm. In the present studies we investigated the kinetics of Gs dissociation and membrane release in plasma membranes from S49 lymphoma cells. We analysed cholate extracts of membranes for alpha s levels by a competitive e.l.i.s.a. with a polyclonal antibody that selectively recognizes monomeric alpha s and we assayed supernatant fractions using both competitive e.l.i.s.a. and immunoblotting. The plasma membranes contained 19.3 +/- 1.4 pmol of alpha s/mg of membrane protein and lacked significant dissociation of Gs and activity of adenylate cyclase in the absence of guanine nucleotides. Mg2+ ions were obligatorily required for isoprenaline-induced dissociation of Gs in plasma membranes and for membrane release of alpha s. At a physiological concentration of free Mg2+ ions (100 microM), 100 microM-GTP induced a slow first-order (k = 0.038 +/- 0.004 min-1) dissociation of 17.8 +/- 1.2 pmol of Gs/mg of membrane protein. A substantial increase in the dissociation rate of Gs was achieved by addition of 1 microM-isoprenaline and 100 microM-GTP; 18.4 +/- 0.9 pmol of Gs/mg of membrane protein was dissociated, with a kappa of 1.49 +/- 0.22 min-1. The effect of isoprenaline on the dissociation rate and on membrane release of Gs was completely blocked by the beta-adrenergic receptor antagonist propranolol. The concentration-response relationship for isoprenaline-induced dissociation during the first 1 min after addition of hormone yielded a kappa act. of 16 +/- 5 nM, whereas the kappa act. for isoprenaline-induced membrane release was 10 nM. We conclude that release of alpha s from plasma membranes is likely to accompany Gs-subunit dissociation and constitutes a potentially important facet of Gs action.

Animals↗
PubMed2001

[Dissociated horizontal deviations (DHD): nomenclature and etiology. An orientating attempt in terminological confusion].

PURPOSE: To classify dissociated horizontal deviations (DHD) based on the etiology of the vergence that causes the dissociation of the squint angle. METHODS: Dissociated strabismus can reliably be diagnosed by a change of the squint angle caused by an alternation in the fixation from one eye to the other, when all the other conditions (head posture, direction of gaze, fixation distance, accommodation) remain unchanged. The decisive diagnostic tool is the reversed fixation test: During monocular fixation with one eye, the squint angle of the other eye is neutralized using a synoptometer or a prism. Then, the fixation is changed to the other eye, which keeps its position behind the prism. If the change in fixation causes a change in the position of the previously fixating eye, the deviation is dissociated. If the position of the previously fixating eye does not change, the deviation is not dissociated. RESULTS: Dissociated strabismus can be detected and differentiated from both comitant and incomitant non dissociated strabismus by the reversed fixation test. The dark red glass test is less sensitive and less specific for dissociated strabismus than the reversed fixation test, if a difference in accommodative convergence is excluded, possible causes of DHD are nystagmus-attenuating convergence, substitution of version eye movement by convergence, and a horizontal side effect of the vertical eye muscles in asymmetric DVD. CONCLUSION: Dissociated strabismus is an effect of vergence which is brought about by the change in the fixation or dominance from one eye to the other eye or in the interocular ratio of afferent input (luminance). Dissociated strabismus can be classified based on its direction or due to its etiology.

Diagnosis, Differential↗
PubMed2006

Dissociation of the OCS+ ion in low-lying electronic states studied using multiconfiguration second-order perturbation theory.

Complete active space self-consistent-field (CASSCF) and multiconfiguration second-order perturbation theory (CASPT2) calculations with atomic natural orbital basis sets were performed to investigate the S-loss direct dissociation of the 1 2Pi(X 2Pi), 2 2Pi(A 2Pi), 1 2Sigma+(B 2Sigma+), 1 4Sigma-, 1 2Sigma-, and 1 2Delta states of the OCS+ ion and the predissociations of the 1 2Pi, 2 2Pi, and 1 2Sigma+ states. Our calculations indicate that the S-loss dissociation products of the OCS(+) ion in the six states are the ground-state CO molecule plus the S+ ion in different electronic states. The CASPT2//CASSCF potential energy curves were calculated for the S-loss dissociation from the six states. The calculations indicate that the dissociation of the 1 4Sigma- state leads to the CO + S+ (4Su) products representing the first dissociation limit; the dissociations of the 1 2Pi, 1 2Sigma-, and 1 2Delta states lead to the CO + S+(2Du) products representing the second dissociation limit; and the dissociations of the 2 2Pi and 1 2Sigma+ states lead to the CO + S+(2Pu) products representing the third dissociation limit. Seams of the 1 2Pi-1 4Sigma-, 2 2Pi-1 4Sigma-, 2 2Pi-1 2Sigma-, 2 2Pi-1 2Delta, and 1 2Sigma(+)-1 4Sigma- potential energy surface intersections were calculated at the CASPT2 level, and the minima along the seams were located. The calculations indicate that within the experimental energy range (15.07-16.0 eV) the 2 2Pi(A 2Pi) state can be predissociated by 1 4Sigma- forming the S+(4Su) ion and can undergo internal conversion to 1 2Pi followed by the direct dissociation of 1 2Pi forming S+(2Du) and that within the experimental energy range (16.04-16.54 eV) the 1 2Sigma+(B 2Sigma+) state can be predissociated by 1 4Sigma- forming the S+(4Su) ion and can undergo internal conversion to 2 2Pi followed by the predissociation of 2 2Pi by 1 2Sigma- and 1 2Delta forming the S+(2Du) ion. These indications are in line with the experimental fact that both the 4Su and 2Du states of the S+ ion can be formed from the 2 2Pi and 1 2Sigma+ states of the OCS+ ion.

Journal Article↗
PubMed2001

Microtubules are involved in glucose-dependent dissociation of the yeast vacuolar [H+]-ATPase in vivo.

The vacuolar [H(+)]-ATPases (V-ATPases) are composed of a peripheral V(1) domain and a membrane-embedded V(0) domain. Reversible dissociation of the V(1) and V(0) domains has been observed in both yeast and insects and has been suggested to represent a general regulatory mechanism for controlling V-ATPase activity in vivo. In yeast, dissociation of the V-ATPase is triggered by glucose depletion, but the signaling pathways that connect V-ATPase dissociation and glucose metabolism have not been identified. We have found that nocodazole, an agent that disrupts microtubules, partially blocked dissociation of the V-ATPase in response to glucose depletion in yeast. By contrast, latrunculin, an agent that disrupts actin filaments, had no effect on glucose-dependent dissociation of the V-ATPase complex. Neither nocodazole nor latrunculin blocked reassembly of the V-ATPase upon re-addition of glucose to the medium. The effect of nocodazole appears to be specifically through disruption of microtubules since glucose-dependent dissociation of the V-ATPase was not blocked by nocodazole in yeast strains bearing a mutation in tubulin that renders it resistant to nocodazole. Because nocodazole has been shown to arrest cells in the G(2) phase of the cell cycle, it was of interest to determine whether nocodazole exerted its effect on dissociation of the V-ATPase through cell cycle arrest. Glucose-dependent dissociation of the V-ATPase was examined in four yeast strains bearing temperature-sensitive mutations that arrest cells in different stages of the cell cycle. Because dissociation of the V-ATPase occurred normally at both the permissive and restrictive temperatures in these mutants, the results suggest that in vivo dissociation is not dependent upon cell cycle phase.

Antineoplastic Agents↗
PubMed2002

Dissociation of the tubulin dimer is extremely slow, thermodynamically very unfavorable, and reversible in the absence of an energy source.

The finding that exchange of tubulin subunits between tubulin dimers (alpha-beta + alpha'beta' <--> alpha'beta + alphabeta') does not occur in the absence of protein cofactors and GTP hydrolysis conflicts with the assumption that pure tubulin dimer and monomer are in rapid equilibrium. This assumption underlies the many physical chemical measurements of the K(d) for dimer dissociation. To resolve this discrepancy we used surface plasmon resonance to determine the rate constant for dimer dissociation. The half-time for dissociation was approximately 9.6 h with tubulin-GTP, 2.4 h with tubulin-GDP, and 1.3 h in the absence of nucleotide. A Kd equal to 10(-11) M was calculated from the measured rate for dissociation and an estimated rate for association. Dimer dissociation was found to be reversible, and dimer formation does not require GTP hydrolysis or folding information from protein cofactors, because 0.2 microM tubulin-GDP incubated for 20 h was eluted as dimer when analyzed by size exclusion chromatography. Because 20 h corresponds to eight half-times for dissociation, only monomer would be present if dissociation were an irreversible reaction and if dimer formation required GTP or protein cofactors. Additional evidence for a 10(-11) M K(d) was obtained from gel exclusion chromatography studies of 0.02-2 nM tubulin-GDP. The slow dissociation of the tubulin dimer suggests that protein tubulin cofactors function to catalyze dimer dissociation, rather than dimer assembly. Assuming N-site-GTP dissociation is from monomer, our results agree with the 16-h half-time for N-site GTP in vitro and 33 h half-life for tubulin N-site-GTP in CHO cells.

Animals↗
PubMed1988

The dissociation rate of unlabelled drugs from receptor sites: a poorly investigated, yet important aspect in receptor research. Studies on the serotonin-S2 receptor.

The labelling by 3H-spiperone of serotonin-S2 receptors in rat frontal cortex tissue adsorbed to glass fibre filters was investigated. For 12 unlabelled serotonin antagonists the dissociation time from serotonin-S2 receptors was measured using rat frontal cortex tissue preparations adsorbed to glass fibre filters. The dissociation half-time varied from 4.8 min for pipamperone to 160 min for ritanserin. The drug-receptor dissociation time was not related to a particular class of chemical structure, or to the lipophilicity or the acid dissociation constant of the drugs. The essential requirement of experimental determination of the drug-receptor dissociation time for each drug individually is illustrated. The possible applications of the knowledge of the drug-receptor dissociation time in in vitro and in vivo receptor studies, in pharmacological and pharmacokinetic studies and in drug design and receptor modelling is discussed. For various serotonin-S2 antagonists, the type of inhibition produced by the drug on 3H-ketanserin binding to serotonin-S2 receptors was determined using suspensions of rat frontal cortical tissue. The observed patterns of inhibition were clearly related to the drug-receptor dissociation times: rapidly dissociating drugs produced competitive inhibition, drugs with dissociation half-times between 15-30 min produced mixed type inhibition, and the very slowly dissociating ritanserin produced non-competitive inhibition.

Animals↗
PubMed1990

Effects of charcoal on dissociation kinetics of nuclear and cytosolic steroid-receptor complexes from hen oviduct.

The observed rate of dissociation of radioactive estradiol from nuclear estrogen-receptor complexes from hen oviduct has been shown to depend to a large extent on the method used to initiate dissociation. The present study indicates that nuclear progesterone receptors display the same pattern of behavior. Dissociation kinetics of nuclear progesterone receptor extracted from hen oviducts were affected by the method of initiation of dissociation; the rate of dissociation at 25 degrees C when dissociation was initiated with unlabeled steroid was three times that observed when dissociation was initiated by addition of a charcoal/dextran suspension. In contrast to nuclear receptors, both estrogen and progesterone receptors prepared from cytosol displayed only a single rate of dissociation, no matter what the method of initiation of dissociation. These results strengthen the idea that nuclear receptors contain a factor or subunit which may be removed by charcoal, which alters the rate of dissociation of steroid from the complex.

Animals↗
PubMedDate not supplied

[Characteristics of carbohydrate metabolism of R-, S- i M-dissociants of Pseudomonas aeruginosa].

R and S dissociants of the hydrocarbon-oxidizing strain Pseudomonas aeruginosa K-2 differed but little in their growth in a minimal defined medium with glucose as the source of carbon and energy. At the same time, the number of cells of M dissociant in the late exponential phase was five orders of magnitude less than that of R and S dissociants. The growth of M dissociant was accompanied by the accumulation of formate in the culture liquid and a concurrent decrease in pH. All three dissociants contained the key enzymes of the Entner-Doudoroff pathway of glucose oxidation; however, the activities of these enzymes, especially 6-phosphogluconate dehydrogenase, were low in M dissociant. Conversely, the activity of formate dehydrogenase in cells of M dissociant was higher than in other dissociants. The activity of 6-phosphogluconate dehydrogenase, a key enzyme of the pentosephosphate pathway of glucose oxidation, was detected only in S dissociant. The peculiarities of the carbohydrate metabolism of M dissociant are probably responsible for its poor growth on glucose and determine the more pronounced anaerobic type of its metabolism.

Carbohydrate Metabolism↗
PubMed1988

Daunomycin-DNA dissociation kinetics.

The dissociation of daunomycin from DNA was examined using a sodium dodecyl sulfate-sequestered stopped flow procedure. Two dissociation processes were observed with calf thymus and bacterial DNA, with approximately 45% of the amplitude associated with the faster process. Both processes were largely independent of DNA sequence for bacterial DNA, comprising 30-70% (G + C) content. The rate of both processes increased by a similar amount with increasing ionic strength. The faster process decreased with decreasing drug loading, whereas the slower process was independent of drug loading. Only one dissociation event was observed for the dissociation of daunomycin from four different synthetic polydeoxynucleotides. All observations are consistent with a parallel model of sodium dodecyl sulfate-induced dissociation of daunomycin from DNA, where the two processes observed reflect two resolvable processes that may be comprised of a series of rate constants for the dissociation of drug from differing environments. The slower process observed with bacterial DNA (0.5-0.7 sec-1) is related to dissociation from preferential 5'-CA DNA-binding sites, whereas the faster process reflects dissociation of drug from lower affinity sites on heterogenous DNA (3.2-4.1 sec-1). Dissociation of daunomycin from four different synthetic polydeoxynucleotides (which did not contain the 5'-CA preferential daunomycin-binding site) exhibited dissociation rates characteristic of low affinity sites (3.3-4.8 sec-1).

Base Composition↗
PubMed1987

Transformation of the 8-9 S molybdate-stabilized estrogen receptor from low-affinity to high-affinity state without dissociation into subunits.

The rate of dissociation of labeled estradiol from [3H] estradiol-8-9 S receptor complexes ([3H]E2-8-9 S ER) molybdate-stabilized was determined in the presence of either an excess of unlabeled hormone ("chase") or of charcoal/dextran suspension ("stripping"). Biphasic dissociation of the hormone was observed in both cases, but the fraction of the fast-dissociating component was dramatically reduced (5% instead of 60%) when stripping was used. As the dissociation patterns were independent of the degree of saturation of the receptor, the results do not favor the possibility of cooperative effects between binding sites in the 8-9 S ER. After pretreatment of cytosol by charcoal at 28 degrees C for 15 min, the dissociation studied by chase displayed only the slowly dissociating component (t1/2 approximately 65 min). This effect was dependent on temperature and influenced by the ligand bound to 8-9 S ER, being pronounced with estradiol (E2) and absent with [3H]4-hydroxytamoxifen. The slow-dissociating component obtained after charcoal treatment was reconverted to fast-dissociating state by adding dithiothreitol or by incubation with cytosol at 20 degrees C. The charcoal treatment did not change the sedimentation coefficient (approximately 9 S) and the Stokes radius (approximately 7 nm) of the [3H]E2-8-9 S ER, and the slow-dissociating form obtained did not bind to DNA-cellulose either in the presence or absence of molybdate ions. Thus there are likely small but functionally significant changes of structure in the 8-9 S ER which remain in a non-DNA-binding form, whereas the rate of estradiol dissociation is modified.

Animals↗
PubMed1976

Tetramer-dimer dissociation in homoglobin and the Bohr effect.

The pH dependence of the apparent tetramer to dimer dissociation constant has been determined at 20 degrees for both oxy- and deoxyhemoglobins A and Kansas. These measurements were made by three different procedures: gel chromatography, sedimentation velocity, and kinetic methods in either of three buffer systems: 0.05 M cacodylate, Tris, or glycine with 1 mM EDTA and 0.1 M NaCl between pH 6.5 and 11. The tetramer-dimer dissociation constant of human oxyhemoglobin A decreases from about 3.2 X 10(-6) M at pH 6.0 to about 3.2 X 10(-8) M at pH 8.5. The slope of this line indicates that the dissociation of tetramer to dimer is accompanied by the uptake of about 0.6 protons per mol of tetramer in this region. The corresponding dissociation constant for deoxyhemoglobin in the same pH region increases apparently almost linearly from 1.0 x 10(-12) M at pH 6.5 to about 1.0 x 10(-5) M at pH 11. To dimer is associated with the release of about 1.6 protons per mol of tetramer. Comparison of these data with the known proton release accompanying the oxygenation of tetramers confirms that the pH dependence of oxygen binding by dimers must be very small. The present data predict that the overall proton release or uptake per oxygen bound by dimer should be less than 0.1. The tetramer-dimer dissociation equilibria of oxy- and deoxyhemoglobins above pH 8.5 have identical pH dependences. In this range the dissociation constant of deoxy-Hb is about one-tenth that of oxyhemoglobin. Human oxyhemoglobin Kansas is known to have an enhanced tetramer-dimer dissociation compared with that of hemoglobin A. Below pH 8.5 the tetramer-dimer dissociation constant of Hb Kansas is about 400 times greater than that of HbA in the absence of phosphate buffers. In contrast, the tetramer-dimer dissociation constants of deoxyhemoglobins A and Kansas appear to be identical. These findings are consistent with previous structural observations on these hemoglobins. The data on the tetramer-dimer dissociation of human hemoglobin were used to calculate the total free energy of binding of oxygen to the tetramer and the median oxygen pressure on the basis of fundamental linkage relations and a pH-independent estimate of the total free energy of binding oxygen to dimer. Simulated oxygen binding curves were generated with the equations of Ackers and Halvorson (Ackers, G. K., and Halvorson, H. (1974) Proc. Natl. Acad. Sci. U.S.A. 71, 4312-4316) by making two assumptions: (a) that the dimers are noncooperative and pH-independent in O2 binding and (b) that the distribution of cooperative energy in the oxygenation of tetramers is independent of pH. We have compared these simulations with experimental data obtained at low protein concentrations (30 to 124 muM heme) to show that the variation in oxygen affinity with pH can be described in terms of the subunit equilibria. We conclude that an accurate analysis of the contributions of individual oxygen binding steps to the Bohr effect cannot be made without considering the contributions of the dimers to oxygen binding...

Hemoglobins↗
PubMed2003

Dissociative experiences of women child abuse survivors: a selective constructivist review.

A selective literature review of dissociation in women abuse survivors was under-taken from a feminist, constructivist perspective. Dissociation has been conceptualized many ways historically. Current understandings of dissociative phenomena are diverse, as reflected in the research and treatment literature. Dissociation has been linked to physical and psychological problems, including major mental illnesses, pelvic pain, somatization disorders, and eating disorders. There has been a preoccupation with rare but fascinating extremes of dissociation, such as multiple personality disorder, with less emphasis on more frequently seen types of dissociation, such as depersonalization and derealization. Views of dissociation as it occurs in women child abuse survivors affect their autonomy and perceived credibility and determine treatment trajectories. Questions remain as to what aspects and types of dissociation are "pathological." There is evidence that dissociation may be a commonplace human experience in the general population. Implications for theory, research, and practice are included.

Adaptation, Psychological↗
PubMed1992

The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein.

The ras-related protein, CDC42Hs, is a 22-kDa GTP-binding protein which is the human homolog of a Saccharomyces cerevisiae yeast-cell-division cycle protein. In attempting to isolate and biochemically characterize mammalian proteins capable of regulating various activities of CDC42Hs, we have identified an activity in bovine brain cytosol which effectively inhibits the dissociation of [3H]GDP from the platelet- or the Spodoptera frugiperda-expressed CDC42Hs protein. The purification of this activity was achieved by a series of steps which included ammonium sulfate fractionation, DEAE-Sephacel, Mono-Q, and Mono-S chromatographies. The purified CDC42Hs regulatory protein has an apparent molecular weight of 28,000, and cyanogen bromide-generated peptide sequences of this protein were identical to sequences from the carboxyl-terminal portion of rho-GDP-dissociation inhibitor (rho-GDI) (Fukumoto, Y., Kaibuchi, K., Hori, Y., Fujioka, H., Araki, S., Ueda, T., Kikuchi, A., and Takai, Y. (1990) Oncogene 5, 1321-1328). In addition, an Escherichia coli-expressed, glutathione S-transferase-rho-GDI fusion protein fully substitutes for the GDI which we have purified from bovine brain in its ability to inhibit GDP dissociation from CDC42Hs. These findings suggest either that a common regulatory protein (GDI) is capable of inhibiting GDP dissociation from the rho and CDC42Hs proteins or that these two GTP-binding proteins interact with GDI proteins of very similar structure. The purified brain GDI protein shows little ability to inhibit GDP dissociation from the E. coli-expressed CDC42Hs and is capable of only a very weak inhibition of the dissociation of [35S]guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) from the Spodoptera frugiperda-expressed CDC42. However, brain GDI very effectively inhibits the ability of the human dbl oncogene product to catalyze GDP dissociation from CDC42Hs. In addition to influencing guanine nucleotide association with CDC42Hs, the purified brain GDI protein also appears to catalyze the dissociation of CDC42Hs from the plasma membranes of human placenta and human epidermoid carcinoma (A431) cells. This effect by the GDI protein is observed whether the membrane-associated CDC42Hs is preincubated with GDP, GTP gamma S, or no guanine nucleotides, and occurs over a similar concentration range as that necessary for the inhibition of the intrinsic GDP dissociation.

Amino Acid Sequence↗
PubMed2005

State dissociation in bulimic eating disorders: an experimental study.

BACKGROUND: Dissociation and binge eating appear to have equivalent functions, lowering awareness of generalized threat and negative self-esteem. Dissociation can be a general characteristic of the individual, present in all situations (i.e., a trait), or it can be a time-limited reaction to a specific situation (i.e., a state). Previous studies have shown that the subliminal presentation of threat cues leads to increased bulimic behaviors. This experimental study examines whether dissociation is activated under similar conditions, thus testing whether dissociation is a reactive state in bulimic women, as well as a trait. METHOD: The participants were 24 bulimic and 26 nonclinical women, each of whom completed the Eating Disorders Inventory and the Dissociative Experiences Scale. Each woman was exposed to subliminal neutral and threat cues, before completing the subjective component of the Clinician-Administered Dissociation Scale and a measure of anxiety and mood (the Hospital Anxiety and Depression Scale). RESULTS: The subliminal threat cue significantly increased state dissociation (particularly derealization levels) in the bulimic women but had no effect on the nonclinical group. There was no impact on mood. DISCUSSION: State dissociation appears to play an integral role in the bulimic process, but further studies are needed to determine the causal structure in that relationship and whether it applies in other disorders. Future clinical practice should be directed towards the identification and treatment of state dissociation in therapy.

Adult↗
PubMed2001

MMPI profile characteristics of women with varying levels of normal dissociation.

MMPI-2 correlates of normal dissociation as measured by the absorption subscale items of the Dissociative Experiences Scale (DES) were examined in patients with diagnoses in the dissociative spectrum (n = 119) and not in the dissociative spectrum (n = 97). All patients completed the MMPI-2 and DES and were assigned to subgroups based on a cut-off score of 30 on normal dissociation. Results indicated that normal dissociation was unusually prominent among patients with mental disorders. The MMPI profiles of those with high imbalances of normal dissociation were skewed in the direction of more pathology across a broad range of mental symptoms. This was true for both dissociative and nondissociative patients. These findings provide preliminary evidence that high imbalances in normal dissociation may be related to psychopathology of a general nature.

Adult↗
PubMed1996

Factors related to dissociation among patients with gastrointestinal complaints.

OBJECTIVES: Several recent reports have suggested that the process of dissociation is independently associated with several distressing conditions such as psychiatric diagnoses, somatization, current psychological distress, and past sexual and physical victimization. These studies, however, have not taken into account possible shared variance between these variables. Is dissociation uniquely related to each of these outcomes or do they, as a group, have common underlying factors that account for the relationship with dissociation? METHOD: As part of a larger study of gastroenterology clinic patients with irritable bowel syndrome and patients with inflammatory bowel disease (n = 103), we used stepwise multiple regression to select the factors most associated with dissociation, while controlling for the effects of other variables. Variable domains included demographics, psychiatric diagnoses, personality factors, functional disability, and trauma history. These domains as well as individual variables within these domains were systematically evaluated for their unique contribution to the prediction of dissociation as measured by the Dissociative Experiences Scale (DES). RESULTS: The best multivariable model for estimating dissociation magnitude included severe child sexual abuse, perceived physical disability, and lifetime dysthymia, alcoholism, and generalized anxiety disorder. These factors accounted for 37% of the variance in DES score and increased the correct classification of patients as either low-, middle-, or high-level dissociators. CONCLUSIONS: Dissociation among this convenience sample of IBS and IBD patients is a long-term coping pattern that is associated primarily with past sexual trauma, chronic emotional distress, alcoholism, and physical disability. Prospective studies are needed to test whether these findings also occur in other more generalizable samples.

Adolescent↗