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R Gaudet

Publications and source records attributed to R Gaudet.

At least 19 recordsLinked to original sources
PubMed2001

Structure of the ABC ATPase domain of human TAP1, the transporter associated with antigen processing.

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.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2.

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.

Amino Acid Sequence↗
PubMed2001

Identification of a structural motif that confers specific interaction with the WD40 repeat domain of Arabidopsis COP1.

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.

Amino Acid Sequence↗
PubMed2001

Correlations between serum assays of human chorionic gonadotrophin (hCG) and human placental lactogen (hPL) and pre-eclampsia or intrauterine growth restriction (IUGR) among nulliparas younger than 38 years.

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.

Adult↗
PubMed2001

Virus subversion of immunity: a structural perspective.

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.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

[Risk factors in pre-eclampsia].

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.

Aspirin↗
PubMed1999

A molecular mechanism for the phosphorylation-dependent regulation of heterotrimeric G proteins by phosducin.

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.

Animals↗
PubMed1997

Structural aspects of heterotrimeric G-protein signaling.

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.

Animals↗
PubMed1996

Crystal structure at 2.4 angstroms resolution of the complex of transducin betagamma and its regulator, phosducin.

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.

Amino Acid Sequence↗
PubMedDate not supplied

Prenatal diagnosis of a congenital bladder diverticulum. Case report and benefits of prenatal diagnosis.

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.

Adult↗