Homozygous FIBP nonsense variant responsible of syndromic overgrowth, with overgrowth, macrocephaly, retinal coloboma and learning disabilities.

The acidic fibroblast growth factor (FGF) intracellular binding protein (FIBP) interacts directly with the fibroblast growth factor FGF1. Although FIBP is known to be implicated in the FGF signaling pathway, its precise function remains unclear. Gain-of-function variants in several FGF receptors (FGFRs) are implicated in a wide spectrum of growth disorders from achondroplasia to overgrowth syndromes. In a unique case from a consanguineous union presenting with overgrowth, macrocephaly, retinal coloboma, large thumbs, severe varicose veins and learning disabilities, exome sequencing identified a homozygous nonsense FIBP variant. The patient's fibroblasts exhibit FIBP cDNA degradation and an increased proliferation capacity compared with controls. The phenotype defines a new multiple congenital abnormalities (MCA) syndrome, overlapping with the heterogeneous group of overgrowth syndromes with macrocephaly. The different clinical features can be explained by the alteration of the FGFR pathway. Taken together, these results suggest the implication of FIBP in a new autosomal recessive MCA.

The mechanism of cyclic electron flow.

Apart from the canonical light-driven linear electron flow (LEF) from water to CO2, numerous regulatory and alternative electron transfer pathways exist in chloroplasts. One of them is the cyclic electron flow around Photosystem I (CEF), contributing to photoprotection of both Photosystem I and II (PSI, PSII) and supplying extra ATP to fix atmospheric carbon. Nonetheless, CEF remains an enigma in the field of functional photosynthesis as we lack understanding of its pathway. Here, we address the discrepancies between functional and genetic/biochemical data in the literature and formulate novel hypotheses about the pathway and regulation of CEF based on recent structural and kinetic information.

Individual assignments of the heme resonances in the 360 MHz 1H NMR spectra of cytochrome c-557 from Crithidia oncopelti.

With the use of nuclear Overhauser effects, spin decoupling and saturation transfer experiments individual assignments for numerous resonances of the heme group in the 360 MHz 1H NMR spectra of reduced and oxidized cytochrome c-557 from Crithidia oncopelti were obtained. These data provide direct evidence that the heme substituent in position 2 is a vinyl group. They further show that in spite of the different covalent structures of the heme groups the heme crevice and the electronic heme structure in the oxidized state are nearly identical in cytochrome c-557 and in mammalian cytochromes c.

Crystal structure of neutral protease from Bacillus cereus refined at 3.0 A resolution and comparison with the homologous but more thermostable enzyme thermolysin.

Neutral protease from Bacillus cereus exhibits a 73% amino acid sequence homology to thermolysin, for which an accurate crystal structure exists. The B. cereus enzyme is, however, markedly less thermostable. The neutral protease was crystallized and diffraction data to 3.0 A resolution were recorded by oscillation photography. The crystal structure was solved by molecular replacement methods using thermolysin as a trial molecule. The solution was improved by rigid-body refinement and model rebuilding into electron density omit-maps. The atomic co-ordinates were refined to R = 21.7% at 3.0 A resolution. Comparison of the resultant model with the thermolysin structure shows that the two enzymes are very similar with a root-mean-square deviation between equivalent C alpha-atoms of 0.88 A. The gamma-turn found in thermolysin is transformed into a beta-turn in the neutral protease by the insertion of a glycine residue. There appear to be no contributions to the enhanced thermostability of thermolysin from additional salt bridges, whereas contributions in the form of extra hydrogen bonding interactions could be important. Other factors that may affect thermostability include the two glycine to alanine exchanges and perturbations in the environment of the double calcium site.

Domain closure in mitochondrial aspartate aminotransferase.

The subunits of the dimeric enzyme aspartate aminotransferase have two domains: one large and one small. The active site lies in a cavity that is close to both the subunit interface and the interface between the two domains. On binding the substrate the domains close together. This closure completely buries the substrate in the active site and moves two arginine side-chains so they form salt bridges with carboxylate groups of the substrate. The salt bridges hold the substrate close to the pyridoxal 5'-phosphate cofactor and in the right position and orientation for the catalysis of the transamination reaction. We describe here the structural changes that produce the domain movements and the closure of the active site. Structural changes occur at the interface between the domains and within the small domain itself. On closure, the core of the small domain rotates by 13 degrees relative to the large domain. Two other regions of the small domain, which form part of the active site, move somewhat differently. A loop, residues 39 to 49, above the active site moves about 1 A less than the core of the small domain. A helix within the small domain forms the "door" of the active site. It moves with the core of the small domain and, in addition, shifts by 1.2 A, rotates by 10 degrees, and switches its first turn from the alpha to the 3(10) conformation. This results in the helix closing the active site. The domain movements are produced by a co-ordinated series of small changes. Within one subunit the polypeptide chain passes twice between the large and small domains. One link involves a peptide in an extended conformation. The second link is in the middle of a long helix that spans both domains. At the interface this helix is kinked and, on closure, the angle of the kink changes to accommodate the movement of the small domain. The interface between the domains is formed by 15 residues in the large domain packing against 12 residues in the small domain and the manner in which these residues pack is essentially the same in the open and closed structures. Domain movements involve changes in the main-chain and side-chain torsion angles in the residues on both sides of the interface. Most of these changes are small; only a few side-chains switch to new conformations.(ABSTRACT TRUNCATED AT 400 WORDS)

Prostaglandin H synthase: implications for membrane structure.

The crystal structure of the membrane protein prostaglandin H synthase (PGHS) provides strong evidence for the existence of monotopic membrane proteins: PGHS seems to interact with the membrane via a motif of amphipathic helices positioned parallel to the plane of the membrane. The orientation of this unique membrane binding motif is fixed in space by an epidermal growth factor(EGF)-like module on its amino-terminal end and by the catalytic domain at its carboxy-terminal end. The catalytic domain of PGHS has a high structural homology to other mammalian heme peroxidases.

[Prognostic value of nutritional parameters in gastrectomy for cancer: a study of 203 cases]. / Intérêt pronostique des paramètres nutritionnels lors de la gastrectomie pour cancer: étude de 203 patients.

Two hundred and three patients underwent a gastrectomy for 1981 to 1985, as a treatment for gastric carcinoma. This retrospective study focuses on survival and the prognostic value of oncological features as topography, local involvement and size of the tumour, and nutritional features as albuminemia, prealbuminemia and weight loss. Although prealbuminemia and weight loss have a prognostic value, albuminemia has not this classical value. These results show the great importance of the peri-operative nutrition, and lead to criticisms about albuminemia, which is modified by deshydratation and extra-vascular diffusion.

[Intra-digestive fermentation in intestinal malabsorption syndromes: relations with elevated serum activity of gamma-glutamyl-transpeptidase]. / Fermentation intra-digestive au cours des syndromes de malabsorption intestinale: relations avec l'augmentation de l'activité sérique de la gamma-glutamyl-transpeptidase.

UNLABELLED: The aim of this prospective study was to examine the relationship between gastrointestinal ethanol production ("Mei-Tei-Sho" syndrome described in Japan) and biological liver dysfunction associated with intestinal malabsorption syndromes. METHODS: Sixty-five patients with malabsorption-diarrhea underwent 98 simultaneous measurements of plasma gamma-glutamyl-transpeptidase and of faecal ethanol concentrations; in 5 cases, ethanolemia and faecal ethanol concentrations were measured after a 250 g rice-meal; in 1, ethanol concentration was measured in a sample of caecal liquid in hours following local instillation of fructose (40 g). RESULTS: Faecal ethanol was detected at least once in 60/65 patients (74/98 measurements, maximum 3.50 g*L-1), more often (98.0%, P < 0.001) in 51 patients with gamma-glutamyl-transpeptidase above 38 IU/L. Eating rice increased the faecal ethanol concentration in 5 patients, 2 of whom had measurable ethanolemia (0.20 and 0.47 g*L-1). Ileo-caecal ethanol concentration following local fructose instillation was 11.8 g*L-1. CONCLUSION: Endogenous gastrointestinal ethanol production contributes to elevated gamma-glutamyl-transpeptidase activity observed during malabsorption syndromes.

[Measurement of energy expenditure at rest in nutritional disorders. Study in 229 patients]. / Mesure de la dépense énergétique de repos au cours de désordres nutritionnels. Etude chez 229 patientes.

Resting energy expenditure was measured by indirect calorimetry, and body composition was evaluated by electrical body impedance analysis in 229 female patients with anorexia nervosa, cancer, non tumoral disease, obesity, and 42 healthy women. Results were compared with theoretical formulas based on anthropometry, and expressed by kilogram of body weight and lean body mass. Each group was compared with each other and with controls. Resting energy expenditure of controls is quite identical with the theoretical value; it is very low for anorectic patients, high for obese patients, high during non tumoral diseases, and higher during neoplastic diseases. Respiratory quotient shows catabolism of carbohydrates in anorectic patients, and lipid catabolism in other patients. Results are compared with literature data, and pathophysiological mechanisms and clinical use of the method are discussed.

The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.

The three-dimensional structure of prostaglandin H2 synthase-1, an integral membrane protein, has been determined at 3.5 A resolution by X-ray crystallography. This bifunctional enzyme comprises three independent folding units: an epidermal growth factor domain, a membrane-binding motif and an enzymatic domain. Two adjacent but spatially distinct active sites were found for its haem-dependent peroxidase and cyclooxygenase activities. The cyclooxygenase active site is created by a long, hydrophobic channel that is the site of non-steroidal anti-inflammatory drug binding. The conformation of the membrane-binding motif strongly suggests that the enzyme integrates into only one leaflet of the lipid bilayer and is thus a monotopic membrane protein.

Crystallization of the photosystem I reaction centre.

The reaction centre of the photosynthetic membrane complex photosystem I (PSI) from the thermophilic cyanobacterium Phormidium laminosum was found to crystallize under a range of conditions. The crystallization method, which can occur in the presence of larger detergent molecules than those used previously for the crystallization of membrane proteins, is presented in this report. Several crystal forms have been observed, and some of these show birefringence and linear dichroism. Optical measurements on crystals thicker than 5 microm were severely restricted because of the very high chlorophyll density within the crystals, but linear dichroism measurements on thin single crystals were possible and the results are presented here. By comparing the data with earlier measurements on oriented PSI complexes, a working model for the orientation of the PSI complexes within the crystal could be proposed. The PSI reaction centre is one of the largest and most complex membrane protein units that have been crystallized to date.