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A Aberg

Publications and source records attributed to A Aberg.

At least 19 recordsLinked to original sources
PubMed1997

The crystal structure of the signal recognition particle Alu RNA binding heterodimer, SRP9/14.

The mammalian signal recognition particle (SRP) is an 11S cytoplasmic ribonucleoprotein that plays an essential role in protein sorting. SRP recognizes the signal sequence of the nascent polypeptide chain emerging from the ribosome, and targets the ribosome-nascent chain-SRP complex to the rough endoplasmic reticulum. The SRP consists of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) and a single 300 nucleotide RNA molecule. SRP9 and SRP14 proteins form a heterodimer that binds to the Alu domain of SRP RNA which is responsible for translation arrest. We report the first crystal structure of a mammalian SRP protein, that of the mouse SRP9/14 heterodimer, determined at 2.5 A resolution. SRP9 and SRP14 are found to be structurally homologous, containing the same alpha-beta-beta-beta-alpha fold. This we designate the Alu binding module (Alu bm), an additional member of the family of small alpha/beta RNA binding domains. The heterodimer has pseudo 2-fold symmetry and is saddle like, comprising a strongly curved six-stranded amphipathic beta-sheet with the four helices packed on the convex side and the exposed concave surface being lined with positively charged residues.

Amino Acid Sequence↗
PubMed1997

Crystal structure analysis of the activation of histidine by Thermus thermophilus histidyl-tRNA synthetase.

The crystal structure at 2.7 A resolution of histidyl-tRNA synthetase (HisRS) from Thermus thermophilus in complex with its amino acid substrate histidine has been determined. In the crystal asymmetric unit there are two homodimers, each subunit containing 421 amino acid residues. Each monomer of the enzyme consists of three domains: (1) an N-terminal catalytic domain containing a six-stranded antiparallel beta-sheet and the three motifs common to all class II aminoacyl-tRNA synthetases, (2) a 90-residue C-terminal alpha/beta domain which is common to most class IIa synthetases and is probably involved in recognizing the anticodon stem-loop of tRNA(His), and (3) a HisRS-specific alpha-helical domain inserted into the catalytic domain, between motifs II and III. The position of the insertion domain above the catalytic site suggests that it could clamp onto the acceptor stem of the tRNA during aminoacylation. Two HisRS-specific peptides, 259-RGLDYY and 285-GGRYDG, are intimately involved in forming the binding site for the histidine, a molecule of which is found in the active site of each monomer. The structure of HisRS in complex with histidyl adenylate, produced enzymatically in the crystal, has been determined at 3.2 A resolution. This structure shows that the HisRS-specific Arg-259 interacts directly with the alpha-phosphate of the adenylate on the opposite side to the usual conserved motif 2 arginine. Arg-259 thus substitutes for the divalent cation observed in seryl-tRNA synthetase and plays a crucial catalytic role in the mechanism of histidine activation.

Amino Acid Sequence↗
PubMed1997

Pre-eclampsia is a potent risk factor for deterioration of retinopathy during pregnancy in Type 1 diabetic patients.

The aim of the present study was to examine the influence of pregnancy on deterioration of retinopathy in patients with Type 1 diabetes mellitus. Sixty-five pregnant Type 1 diabetic women attending the University Hospital in Lund were studied retrospectively. The degree of retinopathy, and levels of HbA1c and blood pressure 12 months before, during, and 6 months after pregnancy were compared of those of 56 non-pregnant Type 1 diabetic women matched for age and duration of diabetes. For all patients, sight-threatening deterioration of retinopathy did not differ between the pregnancy group (9/65) and the control group (6/56). Over time, pregnant patients had lower HbA1c levels than controls (p < 0.001). Pregnant patients with sight-threatening deterioration of retinopathy had higher HbA1c levels than those without (p = 0.028 and the decrement in HbA1c between the 6-14th and the 20th week of gestation was more pronounced (p = 0.006). In those patients who developed pre-eclampsia during pregnancy, deterioration of retinopathy ocurred more frequently compared to those without pre-eclampsia (4/8 vs 5/65; p = 0.005). In conclusion, sight-threatening deterioration of retinopathy was not more common during pregnancy in IDDM patients than among age- and duration-matched control patients. In pregnant patients, deterioration of retinopathy was associated with the pregestational degree of metabolic control as well as with a rapidly improved glycaemic control acheived during pregnancy. Among those in whom deterioration occurred during pregnancy, pre-eclampsia was a potent risk factor.

Adult↗
PubMed1997

Impaired glucose tolerance during pregnancy is associated with increased fetal mortality in preceding sibs.

OBJECTIVES: To analyze whether women with a diagnosis of gestational diabetes in the current pregnancy had an increased rate of stillbirths or of large for gestational age infants in previous pregnancies without an overtly present/diagnosed gestational diabetes. DESIGN: A case-control analysis with two controls for each case, matched for year of delivery, maternal age (5 year class), and parity. MATERIAL AND METHODS: All women with a diagnosis of gestational diabetes and delivered between 1987 and 1992 were identified from the Swedish Medical Birth Registry. For each woman, the first delivery with that diagnosis was used as proband case (n = 3,958). To each case and control, all previous sibs since 1973 were identified. Comparisons were made between cases and controls but also between sibs of cases and sibs of controls. RESULTS: No significant difference was found in stillbirth rate between cases and controls (OR 1.33, CL 0.64;2.77). The rate of intrauterine deaths was significantly increased among previous sibs of the cases compared with the sibs of the controls: after stratification for year of birth, maternal age and parity an odds ratio of 1.56 (95% CL 1.12;2.19) was found. Infants born of women with gestational diabetes were heavier (mean 145 g, 95% CL 123;168 g). Similar differences were seen between immediately previous sibs of cases and controls (mean 155 g, 95% CL 127;183 g). CONCLUSIONS: The figures indicate that in pregnancies before a delivery with gestational diabetes the perinatal prognosis was significantly poorer than expected which could be due to the presence of undiagnosed and untreated gestational diabetes. The results argue for an improved screening for gestational diabetes during pregnancy.

Abortion, Spontaneous↗
PubMed1996

Crystal structure of reduced protein R2 of ribonucleotide reductase: the structural basis for oxygen activation at a dinuclear iron site.

BACKGROUND: Ribonucleotide reductases (RNRs) catalyze the formation of the deoxyribonucleotides that are essential for DNA synthesis. The R2 subunit of Escherichia coli RNR is a homodimer containing one dinuclear iron centre per monomer. A tyrosyl radical is essential for catalysis, and is formed via a reaction in which the reduced, diferrous form of the iron centre activates dioxygen. To help understand the mechanism of oxygen activation, we examined the structure of the diferrous form of R2. RESULTS: The crystal structures of reduced forms of both wild type R2 and a mutant of R2 (Ser211--> Ala) have been determined at 1.7 A and 2.2 A resolution, respectively. The diferrous iron centre was compared to the previously determined structure of the oxidized, diferric form of R2. In both forms of R2 the iron centre is coordinated by the same carboxylate dominated ligand sphere, but in the reduced form there are clear conformational changes in three of the carboxylate ligands and the bridging mu-oxo group and two water molecules are lost. In the reduced form of R2 the coordination number decreases from six to four for both ferrous ions, explaining their high reactivity towards dioxygen. The structure of the mutant Ser211--> Ala, known to have impaired reduction kinetics, shows a large conformational change in one of the neighbouring helices although the iron coordination is very similar to the wild type protein. CONCLUSIONS: Carboxylate shifts are often important for carboxylate coordinated metal clusters; they allow the metals to achieve different coordination modes in redox reactions. In the case of reduced R2 these carboxylate shifts allow the formation of accessible reaction sites for dioxygen. The Ser211--> Ala mutant displays a conformational change in the helix containing the mutation, explaining its altered reduction kinetics.

Carboxylic Acids↗
PubMed1996

Crystallization and preliminary crystallographic analysis of the signal recognition particle SRPphi14-9 fusion protein.

The SRPphi14-9 fusion protein, which can functionally replace the SRP9/14 heterodimer in the mammalian signal recognition particle (SRP), has been crystallized using the vapor diffusion method. Four different crystal forms were grown. SRPphi14-9 form IV crystals belong to the space group P4(1)22/ P4(3)22 with cell parameters a = b = 69.7 Angstroms, c = 95.7 Angstroms, alpha = beta = gamma = 90 degrees. A complete data set to 2.8 Angstroms resolution with an Rsym on intensities of 7.0% was collected on a single flash-frozen crystal.

Amino Acid Sequence↗
PubMed1996

Crystallization and preliminary X-ray analysis of the 9 kDa protein of the mouse signal recognition particle and the selenomethionyl-SRP9.

Two different crystal forms of the 9 kDa protein of the signal recognition particle (SRP9) have been prepared by the hanging drop vapor diffusion technique using 28% (w/v) PEG8000 or 28% saturated ammonium sulphate as precipitant. The crystals are hexagonal bipyramids with average dimensions of 0.2 X 0.1 X 0.1 mm(3) and they diffract to a resolution of 2.3 Angstroms. They belong to the space groups P6(2)22/P6(4)22 or P3(1)21/P3(2)21 with cell dimensions a = b = 63.0 Angstroms, and c = 111.5 Angstroms. Crystals have also been grown from the selenomethionyl protein and multiwavelength data sets have been collected.

Animals↗
PubMed1996

Glucose levels and insulin secretion during a 75 g glucose challenge test in normal pregnancy.

OBJECTIVES: The aim of the study was to evaluate glucose levels and insulin secretion early in pregnancy and at a time when gestational diabetes mellitus frequently occurs in order to define reference values for glucose tolerance during pregnancy. The results were also related to maternal factors that might identify subjects at risk of developing gestational diabetes mellitus as well as foetal factors that might be a result of impaired glucose tolerance during pregnancy. DESIGN: A prospective study. SETTING: All Caucasian women attending one antenatal out-patient care unit were offered a 75 g oral glucose tolerance test at the 17th and 32nd week of gestation. SUBJECTS: A total of 586 consecutive pregnant women were included in the study. All 586 women were examined by repeated blood glucose measurements and 298 agreed to perform oral glucose tolerance tests as well. MAIN OUTCOME MEASURES: Venous whole blood glucose values were measured in the fasting state and in samples obtained 15, 30, 45, 60, 75, 90 and 120 min after oral intake of 75 g glucose. Serum insulin and C-peptide were also measured at these times. In all subjects, a random blood glucose sample was taken at the first visit, and thereafter at the 20th, 30th and 36th week of gestation. Information was also obtained from all subjects regarding body mass index, weight gain during pregnancy, smoking habits, family history of diabetes and hypertension, hypertension during pregnancy, past obstetric history, parity, and fetal outcome. RESULTS: The glucose tolerance was significantly impaired at the 32nd week of gestation compared with the 17th week of gestation. The mean +2SD 2 h glucose value during the oral glucose tolerance test at the 32nd week of gestation was 8.0 mmol L-1. Impaired glucose tolerance was characterised by increased insulin resistance, with a significant rise in serum insulin and C-peptide concentrations and in the insulin/glucose index during the oral glucose tolerance test at the 32nd week of gestation. Maternal factors associated with an impaired glucose tolerance were a family history of diabetes mellitus, smoking, a weight gain more than 18 kg during pregnancy, and glucosuria, while a family history of hypertension and hypertension present during pregnancy were not. Foetal factors that might be a result of impaired glucose tolerance during pregnancy, e.g. macrosomia and prematurity as well as complicated deliveries such as vacuum extraction/forceps or Caesarean section, all tended to be associated with higher blood glucose values. The same pattern was seen when the Apgar score was < 7. CONCLUSIONS: The results from this study show that the present cut-off values for diagnosis of gestational diabetes mellitus should be revised. Even if some maternal factors might indicate an increased risk for impaired glucose tolerance during pregnancy, they are probably not enough to detect women with gestational diabetes mellitus. Therefore, a screening programme for gestational diabetes should be considered.

Adult↗
PubMed1995

Crystallization of Thermus thermophilus histidyl-tRNA synthetase and its complex with tRNAHis.

Histidyl-tRNA synthetase (HisRS) has been purified from the extreme thermophile Thermus thermophilus. The protein has been crystallized separately with histidine and with its cognate tRNAHis. Both crystals have been obtained using the vapor diffusion method with ammonium sulphate as precipitant. The crystals of HisRS with histidine belong to the spacegroup P2(1)2(1)2 with cell parameters a = 171.3 A, b = 214.7 A, c = 49.3 A, alpha = beta = gamma = 90 degrees. A complete data set to a resolution of 2.7A with an Rmerge on intensities of 4.1% has been collected on a single frozen crystal. A partial data set collected on a crystal of HisRS in complex with tRNAHis shows that the crystals are tetragonal with cell parameters a = b = 232 A, c = 559 A, alpha = beta = gamma = 90 degrees and diffract to about 4.5 A resolution.

Crystallography, X-Ray↗
PubMed1995

A new symphysis-fundus height growth chart based on a well defined female population with ultrasound-dated singleton pregnancies.

BACKGROUND: The aim was to construct a new symphysis-fundus (SF) height growth chart, based on ultrasound-dated singleton pregnancies. METHODS: We made a population-based study of all women, from the catchment areas of three district antenatal clinics, who registered for antenatal care during 1986. The growth of the SF height was measured on 403 women with singleton pregnancies. RESULTS: During pregnancy each woman made on average 14.0 (s.d. 2.8) visits to the antenatal clinic, where the SF height was measured on average 10.4 (s.d. 2.6) times. All but two women had an ultrasound examination. Using proper longitudinal methods a new SF height growth chart was constructed. CONCLUSION: The mean values of the present curve, based on longitudinal data, were almost identical with the mean values of a recently presented curve based on stratified cross-sectional data. Both these Swedish studies were population-based and the pregnancies were ultrasound-dated.

Adult↗
PubMed1994

Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris.

The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving beta blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antianginal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.

Analysis of Variance↗
PubMed1994

The conserved serine 211 is essential for reduction of the dinuclear iron center in protein R2 of Escherichia coli ribonucleotide reductase.

The R2 protein family of class I ribonucleotide reductases contains a highly conserved serine residue close to the essential tyrosyl radical and the dinuclear iron center. In order to test its physiological importance, we have engineered the Ser-211 of Escherichia coli R2 to an alanine and a cysteine residue. The three-dimensional structure of R2 S211A solved to 2.4-A resolution is virtually identical to the wild-type structure apart from the substituted residue. Both mutant proteins contain oxidized dinuclear iron and tyrosyl radical, and their specific enzyme activity per radical are comparable to that of the wild-type protein. In R2 S211A the stability of the tyrosyl radical is substantially decreased, probably caused by movement of Gln-80 into hydrogen bonding distance of Tyr-122. The major defect in R2 S211A, however, is the inability of its iron center to be reduced by enzymic or chemical means, a characteristic not found in R2 S211C. We propose that Ser-211 is needed as a proton donor/transporter during reduction of the iron center of R2, a reaction which in vivo precedes reconstitution of the tyrosyl radical. This offers a physiological explanation for the high conservation of a serine residue at this position in the R2 family.

Amino Acid Sequence↗
PubMed1993

Autocatalytic generation of dopa in the engineered protein R2 F208Y from Escherichia coli ribonucleotide reductase and crystal structure of the dopa-208 protein.

The mutant form Phe-208-->Tyr of the R2 protein of Escherichia coli ribonucleotide reductase contains an intrinsic ferric-Dopa cofactor with characteristic absorption bands at 460 and ca. 700 nm [Ormö, M., de Maré, F., Regnström, K., Aberg, A., Sahlin, M., Ling, J., Loehr, T. M., Sanders-Loehr, J., & Sjöberg, B. M. (1992) J. Biol. Chem. 267, 8711-8714]. The three-dimensional structure of the mutant protein, solved to 2.5-A resolution, shows that the Dopa is localized to residue 208 and that it is a bidentate ligand of Fe1 of the binuclear iron center of protein R2. Nascent apoR2 F208Y, lacking metal ions, can be purified from overproducing cells grown in iron-depleted medium. ApoR2 F208Y is rapidly and quantitatively converted to the Dopa-208 form in vitro by addition of ferrous iron in the presence of oxygen. Other metal ions (Cu2+, Mn2+, Co2+) known to bind to the metal site of wild-type apoR2 do not generate a Dopa in apoR2 F208Y. The autocatalytic generation of Dopa does not require the presence of a tyrosine residue at position 122, the tyrosine which in a wild-type R2 protein acquires the catalytically essential tyrosyl radical. It is proposed that generation of Dopa initially follows the suggested reaction mechanism for tyrosyl radical generation in the wild-type protein and involves a ferryl intermediate, which in the case of the mutant R2 protein oxygenates Tyr 208. This autocatalytic metal-mediated reaction in the engineered R2 F208Y protein may serve as a model for formation of covalently bound quinones in other proteins.

Apoproteins↗
PubMed1993

Unusual clustering of carboxyl side chains in the core of iron-free ribonucleotide reductase.

The principal driving forces of protein folding are the burial of hydrophobic residues in the interior of proteins and the exposure of charged residues at the surface. Charged residues are only occasionally found in the interior, where they form hydrogen bonds to oppositely charged residues or main-chain atoms. Ribonucleotide reductase, a key enzyme in DNA synthesis, catalyses the de novo production of deoxyribonucleotide precursors. It is composed of two different dimeric proteins R1 and R2 (refs 3-5). R2 subunits contain buried iron-centres with each centre formed by two ferric ions coordinated by four carboxylates and two histidine ligands. Iron-free R2, apoR2, is a precursor of active R2 and folds into a stable protein which is transformed into active R2 by ferrous ions and molecular oxygen. Here we show that the iron-free protein does not undergo any major structural changes compared with the iron-containing R2. The effect of this is a clustering of four carboxyl side chains in the interior of the subunit, in contrast to the normal distribution of charged residues in proteins.

Amino Acid Sequence↗