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1.
Cell Death Dis ; 4: e821, 2013 Oct 03.
Article in English | MEDLINE | ID: mdl-24091664

ABSTRACT

Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (ß-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3ß. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3ß inhibitor, and observed the enhanced expression of ß-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the expPABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing expPABPN1. A similar effect on ß-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/ß-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD.


Subject(s)
Lithium Chloride/pharmacology , Lithium Chloride/therapeutic use , Muscular Dystrophy, Oculopharyngeal/drug therapy , Muscular Dystrophy, Oculopharyngeal/pathology , Wnt Signaling Pathway/drug effects , Animals , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Line , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Green Fluorescent Proteins/metabolism , Humans , Lymphocytes/drug effects , Lymphocytes/metabolism , Mice , Muscular Dystrophy, Oculopharyngeal/metabolism , Mutant Proteins/metabolism , Myoblasts/drug effects , Myoblasts/metabolism , Myoblasts/pathology , Poly(A)-Binding Protein I/genetics , Poly(A)-Binding Protein I/metabolism , Protein Transport/drug effects , Trinucleotide Repeat Expansion/genetics , beta Catenin/metabolism
2.
EMBO J ; 20(17): 4964-72, 2001 Sep 03.
Article in English | MEDLINE | ID: mdl-11532960

ABSTRACT

The transporter associated with antigen processing (TAP) is an ABC transporter formed of two subunits, TAP1 and TAP2, each of which has an N-terminal membrane-spanning domain and a C-terminal ABC ATPase domain. We report the structure of the C-terminal ABC ATPase domain of TAP1 (cTAP1) bound to ADP. cTAP1 forms an L-shaped molecule with two domains, a RecA-like domain and a small alpha-helical domain. The diphosphate group of ADP interacts with the P-loop as expected. Residues thought to be involved in gamma-phosphate binding and hydrolysis show flexibility in the ADP-bound state as evidenced by their high B-factors. Comparisons of cTAP1 with other ABC ATPases from the ABC transporter family as well as ABC ATPases involved in DNA maintenance and repair reveal key regions and residues specific to each family. Three ATPase subfamilies are identified which have distinct adenosine recognition motifs, as well as distinct subdomains that may be specific to the different functions of each subfamily. Differences between TAP1 and TAP2 in the nucleotide-binding site may be related to the observed asymmetry during peptide transport.


Subject(s)
ATP-Binding Cassette Transporters/chemistry , ATP-Binding Cassette Transporters/metabolism , Adenosine Triphosphatases/chemistry , Major Histocompatibility Complex , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP Binding Cassette Transporter, Subfamily B, Member 3 , ATP-Binding Cassette Transporters/genetics , Adenosine Triphosphatases/metabolism , Amino Acid Sequence , Bacteria/metabolism , Binding Sites , Cloning, Molecular , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Structure, Secondary , Protein Subunits , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid
3.
Curr Opin Immunol ; 13(4): 442-50, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11498300

ABSTRACT

Over the past year, we have witnessed the discovery of further virus immuno-evasins--proteins that alter the host immune response. Although many of these factors have been described over the past decade, the structural basis underlying their biology has lagged behind. Structural data have now been obtained for several such proteins. Major advances of the past year include the structures of a viral chemokine-binding protein, of an intact viral regulator of complement activation and of an immuno-evasin with its cellular target.


Subject(s)
Virus Diseases/immunology , Viruses/immunology , ATP Binding Cassette Transporter, Subfamily B, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , Amino Acid Sequence , Animals , Chemokines/antagonists & inhibitors , Complement Activation , Cytokines/chemistry , Cytokines/immunology , Genes, MHC Class II , Histocompatibility Antigens Class I/metabolism , Humans , Molecular Sequence Data , Sequence Homology, Amino Acid , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Viral Proteins/chemistry , Viral Proteins/immunology , Viruses/genetics , Viruses/pathogenicity
4.
Proc Natl Acad Sci U S A ; 98(12): 6794-9, 2001 Jun 05.
Article in English | MEDLINE | ID: mdl-11391001

ABSTRACT

Many persistent viruses have evolved the ability to subvert MHC class I antigen presentation. Indeed, human cytomegalovirus (HCMV) encodes at least four proteins that down-regulate cell-surface expression of class I. The HCMV unique short (US)2 glycoprotein binds newly synthesized class I molecules within the endoplasmic reticulum (ER) and subsequently targets them for proteasomal degradation. We report the crystal structure of US2 bound to the HLA-A2/Tax peptide complex. US2 associates with HLA-A2 at the junction of the peptide-binding region and the alpha3 domain, a novel binding surface on class I that allows US2 to bind independently of peptide sequence. Mutation of class I heavy chains confirms the importance of this binding site in vivo. Available data on class I-ER chaperone interactions indicate that chaperones would not impede US2 binding. Unexpectedly, the US2 ER-luminal domain forms an Ig-like fold. A US2 structure-based sequence alignment reveals that seven HCMV proteins, at least three of which function in immune evasion, share the same fold as US2. The structure allows design of further experiments to determine how US2 targets class I molecules for degradation.


Subject(s)
Antigen Presentation , Cytomegalovirus/chemistry , HLA-A2 Antigen/chemistry , Viral Envelope Proteins/chemistry , Amino Acid Sequence , Binding Sites , Endoplasmic Reticulum/chemistry , HLA-A2 Antigen/metabolism , Humans , Molecular Sequence Data , Protein Folding , Viral Envelope Proteins/metabolism
5.
Eur J Obstet Gynecol Reprod Biol ; 95(1): 59-67, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11267722

ABSTRACT

OBJECTIVE: To study the relation between serum human chorionic gonadotrophin (hCG) levels measured at 15-18 weeks and gestational disorders, assess their correlation with the artery uteroplacental Doppler (AUD) at 24 weeks among nulliparas, and assess the predictivity of the hCG/hPL (human placental lactogen) ratio for pre-eclampsia. STUDY DESIGN: Retrospective study of two groups of women younger than 38 years old: one with an elevated serum hCG level (2 MoM (multiples of the median) or more) and a normal fetal karyotype (group A), and the other with a lower hCG level (group B). Within each group, we studied the nulliparas separately (respectively groups AO and BO). We analyzed the double screening, elevated hCG levels with abnormal AUD, for the predicting of hypertensive disorders. RESULTS: Elevated hCG levels were significantly (p<0.05) more prevalent among women who developed gestational diabetes (groups A and AO) and among nulliparas with pregnancy-induced hypertension and pre-eclampsia (AO). Among nulliparas, the combination of the hCG assay and a subsequent Doppler increased the positive predictive value (PPV) of the assay from 19 to 75%, without reducing its negative predictive value (NPV) for gestational vascular disorders. The hCG/hPL ratio did not improve the predictivity of the hCG assay alone for pre-eclampsia. CONCLUSIONS: An hCG level of 2 MoM or more at 15-18 weeks identifies a group of women at risk of gestational vascular disorders; it therefore ought to lead to an AUD at 24 weeks. This double screening should be able to define a population of women at risk of developing a hypertensive disorder, who could thus benefit from a preventive treatment, as aspirin.


Subject(s)
Chorionic Gonadotropin/blood , Fetal Growth Retardation/blood , Placental Lactogen/blood , Pre-Eclampsia/blood , Adult , Birth Weight , Black People , Case-Control Studies , Diabetes, Gestational/blood , Female , Fetal Growth Retardation/diagnosis , Humans , Infant, Newborn , Male , Maternal Age , Parity , Pre-Eclampsia/diagnosis , Predictive Value of Tests , Pregnancy , Sex Ratio , Ultrasonography, Doppler, Color , Ultrasonography, Prenatal , White People
6.
EMBO J ; 20(1-2): 118-27, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11226162

ABSTRACT

Arabidopsis COP1 is a photomorphogenesis repressor capable of directly interacting with the photomorphogenesis-promoting factor HY5. This interaction between HY5 and COP1 results in targeted deg radation of HY5 by the 26S proteasome. Here we characterized the WD40 repeat domain-mediated interactions of COP1 with HY5 and two new proteins. Mutational analysis of those interactive partners revealed a conserved motif responsible for the interaction with the WD40 domain. This novel motif, with the core sequence V-P-E/D-φ-G (φ = hydrophobic residue) in conjunction with an upstream stretch of 4-5 negatively charged residues, interacts with a defined surface area of the ss-propeller assembly of the COP1 WD40 repeat domain through both hydrophobic and ionic interactions. Several residues in the COP1 WD40 domain that are critical for the interaction with this motif have been revealed. The fact that point mutations either in the COP1 WD40 domain or in the HY5 motif that abolish the interaction between COP1 and HY5 in yeast result in a dramatic reduction of HY5 degradation in transgenic plants validates the biological significance of this defined interaction.


Subject(s)
Arabidopsis Proteins , Arabidopsis/physiology , Carrier Proteins/chemistry , Carrier Proteins/metabolism , Plant Proteins/chemistry , Plant Proteins/metabolism , Proteasome Endopeptidase Complex , Ubiquitin-Protein Ligases , Amino Acid Sequence , Arabidopsis/genetics , Binding Sites , Carrier Proteins/genetics , Cloning, Molecular , Computer Graphics , Cysteine , Models, Molecular , Molecular Sequence Data , Mutagenesis , Mutagenesis, Site-Directed , Peptide Hydrolases/metabolism , Plant Proteins/genetics , Plants, Genetically Modified , Protein Structure, Secondary , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Repetitive Sequences, Amino Acid , Repressor Proteins/chemistry , Repressor Proteins/metabolism , Saccharomyces cerevisiae/genetics , Sequence Alignment , Sequence Deletion , Sequence Homology, Amino Acid
7.
Fetal Diagn Ther ; 15(4): 191-7, 2000.
Article in English | MEDLINE | ID: mdl-10867478

ABSTRACT

Cholestasis of pregnancy is a liver disorder that occurs during the second half of pregnancy, causing pruritus and elevated serum bile acid levels. Its etiology remains unknown but probably involves vascular and humoral immune responses, mediated by bile acids. This disorder is associated with substantially increased fetal morbidity and mortality. The most satisfactory treatment consists in delivering the fetus as soon as pulmonary maturation has occurred.


Subject(s)
Cholestasis/complications , Fetal Death/etiology , Fetal Diseases/etiology , Pregnancy Complications , Adult , Bile Acids and Salts/blood , Cholestasis/drug therapy , Female , Fetal Distress , Fetal Growth Retardation , Heart Rate, Fetal , Humans , Meconium , Pregnancy , Ursodeoxycholic Acid/adverse effects , Ursodeoxycholic Acid/therapeutic use
9.
Fetal Diagn Ther ; 14(5): 301-5, 1999.
Article in English | MEDLINE | ID: mdl-10529575

ABSTRACT

A case of congenital bladder diverticulum diagnosed at 37 weeks of gestation (measured from the first day after the last day of the last menstrual period) is reported. Delivery took place 24 h later. A postnatal urologic work-up confirmed the diagnosis of asymptomatic congenital bladder diverticulum. The infant underwent laparotomic surgery at the age of 6 months, with an extravesical diverticulectomy and ureteral reimplantation. There were no complications. This is the first case reported in the literature of a prenatal diagnosis of a congenital bladder diverticulum. This new aspect allows early management and avoidance of the diagnostic meanders to which the discovery of a pelvic mass might lead, as well as the complications that can follow bladder diverticula.


Subject(s)
Diverticulum/congenital , Diverticulum/diagnosis , Prenatal Diagnosis , Urinary Bladder Diseases/congenital , Urinary Bladder Diseases/diagnosis , Adult , Diverticulum/diagnostic imaging , Diverticulum/surgery , Female , Humans , Laparotomy , Pregnancy , Radiography , Ultrasonography, Prenatal , Urinary Bladder Diseases/diagnostic imaging , Urinary Bladder Diseases/surgery
11.
Mol Cell ; 3(5): 649-60, 1999 May.
Article in English | MEDLINE | ID: mdl-10360181

ABSTRACT

Visual signal transduction is a nearly noise-free process that is exquisitely well regulated over a wide dynamic range of light intensity. A key component in dark/light adaptation is phosducin, a phosphorylatable protein that modulates the amount of transducin heterotrimer (Gt alpha beta gamma) available through sequestration of the beta gamma subunits (Gt beta gamma). The structure of the phosphophosducin/Gt beta gamma complex combined with mutational and biophysical analysis provides a stereochemical mechanism for the regulation of the phosducin-Gt beta gamma interaction. Phosphorylation of serine 73 causes an order-to-disorder transition of a 20-residue stretch, including the phosphorylation site, by disrupting a helix-capping motif. This transition disrupts phosducin's interface with Gt beta gamma, leading to the release of unencumbered Gt beta gamma, which reassociates with the membrane and Gt alpha to form a signaling-competent Gt alpha beta gamma heterotrimer.


Subject(s)
Eye Proteins/genetics , GTP-Binding Proteins/chemistry , GTP-Binding Proteins/metabolism , Phosphoproteins/genetics , Vision, Ocular/physiology , Animals , Circular Dichroism , DNA Mutational Analysis , Endopeptidases/metabolism , Eye Proteins/chemistry , Eye Proteins/metabolism , GTP-Binding Protein Regulators , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Mutagenesis/physiology , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Phosphorylation , Protein Kinases/metabolism , Protein Structure, Secondary , Protein Structure, Tertiary , Rats , Rhodopsin/metabolism , Serine
13.
Presse Med ; 28(39): 2189-96, 1999 Dec 11.
Article in French | MEDLINE | ID: mdl-10629700

ABSTRACT

PATIENT-RELATED FACTORS: Multiparous patients with a past history of severe pre-eclampsia are a high risk population which should be identified early in pregnancy. Selection on this criterion alone is however insufficient for large scale screening and prevention because most of the susceptible women are nulliparous. Search for a particular familial or personal history of vascular disorders can be helpful. The usefulness of blood pressure measurements during the second trimester has not been proven. MARKERS: There is a significant association between pre-eclampsia and a large number of biological markers. No one assay can however fulfill the requirements for effective early screening because sensitivity is too low or the rate of false positives is too high, or because the examination is too invasive or costly. DOPPLER ANOMALIES: Doppler exploration of the uterine arteries at 20 to 24 weeks gestation offers satisfactory sensitivity and specificity but the positive predictive value is low. Persistence of a bilateral notch beyond 24 weeks considerably limits the number of false positives. More than half of the patients with this anomaly will develop hypertension during pregnancy. While no one marker fulfills all the prerequisites for effective screening, a combination of several tests may be useful. hCG assay during the second trimester in association with Doppler exploration of the uterine arteries appears to be a promising combination. PREVENTION: Starting with these markers or risk factors, the goal is to develop a prevention scheme using low-dose aspirin, the only evidence-based preventive treatment to date. Further trials are required to test simultaneously the predictive value and impact (versus placebo) of proposed strategies.


Subject(s)
Pre-Eclampsia/diagnosis , Aspirin/administration & dosage , Aspirin/pharmacology , Evidence-Based Medicine , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/pharmacology , Humans , Pre-Eclampsia/diagnostic imaging , Pre-Eclampsia/prevention & control , Pregnancy , Risk Factors , Ultrasonography, Prenatal
16.
Curr Opin Biotechnol ; 8(4): 480-7, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9265729

ABSTRACT

Recently, structures of heterotrimeric G-protein subunits have been determined in isolation, in conjunction with each other, and in complex with their regulators. Along with biochemical information, these structures suggest how G-protein subunits are oriented relative to the membrane surface and relative to seven-transmembrane helix receptors. They also suggest mechanisms for receptor-catalyzed nucleotide exchange.


Subject(s)
GTP-Binding Proteins/chemistry , GTP-Binding Proteins/metabolism , Protein Structure, Secondary , Signal Transduction , Animals , Eye Proteins/chemistry , Eye Proteins/metabolism , GTP-Binding Protein Regulators , Macromolecular Substances , Models, Biological , Models, Structural , Mutagenesis, Site-Directed , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Receptors, Cell Surface/physiology , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism
17.
Cell ; 87(3): 577-88, 1996 Nov 01.
Article in English | MEDLINE | ID: mdl-8898209

ABSTRACT

The crystal structure of transducin's betagamma subunits complexed with phosducin, which regulates Gtbetagamma activity, has been solved to 2.4 angstroms resolution. Phosducin has two domains that wrap around Gtbetagamma to form an extensive interface. The N-terminal domain binds loops on the "top" Gtbeta surface, overlapping the Gtalpha binding surface, explaining how phosducin blocks Gtbetagamma's interaction with Gtalpha. The C-terminal domain shows structural homology to thioredoxin and binds the outer strands of Gtbeta's seventh and first blades in a manner likely to disrupt Gtbetagamma's normal orientation relative to the membrane and receptor. Phosducin's Ser-73, which when phosphorylated inhibits phosducin's function, points away from Gtbetagamma, toward a large flexible loop. Thus phosphorylation is not likely to affect the interface directly, but rather indirectly through an induced conformational change.


Subject(s)
Eye Proteins/chemistry , Models, Molecular , Phosphoproteins/chemistry , Protein Conformation , Transducin/chemistry , Amino Acid Sequence , Animal Population Groups/metabolism , Animals , Cattle , Crystallography, X-Ray , DNA, Complementary/genetics , GTP-Binding Protein Regulators , Humans , Macromolecular Substances , Mice , Molecular Sequence Data , Phosphorylation , Protein Binding , Protein Processing, Post-Translational , Rats , Recombinant Fusion Proteins/chemistry , Rod Cell Outer Segment/chemistry , Sequence Alignment , Sequence Homology, Amino Acid , Species Specificity , Static Electricity , Thioredoxins/chemistry , Yeasts/metabolism
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