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Jeanpierre Cazenave - One of the best experts on this subject based on the ideXlab platform.

  • A three‐base deletion removing a Leucine Residue in a Leucine‐rich repeat of platelet glycoprotein Ibα associated with a variant of Bernard‐Soulier syndrome (Nancy I)
    British Journal of Haematology, 1995
    Co-Authors: Mariejeanne Baas, Franccois Lanza, Agnegs Schwartz, Daniel Hanau, Jerotme Chevalier, Christian Gachet, Marieelisabeth Briquel, Jeanpierre Cazenave
    Abstract:

    : Leucine-rich repeats are conserved structural motifs present in the four components of the human platelet glycoprotein Ib/IX/V complex receptor for the adhesive protein von Willebrand factor. The absence or abnormality of this complex is responsible for Bernard-Soulier disease, an autosomal recessive bleeding disorder. We report a deletion of Leucine 179, located in a highly conserved position of the seventh Leucine-rich repeat of GPIb alpha, found in a variant form of Bernard-Soulier disease (Bernard-Soulier Nancy I). Three affected siblings of a family were characterized by absence of ristocetin-induced platelet agglutination, although ADP aggregation was normal. Flow cytometry studies showed detectable amounts of all four members of the GPIb/IX/V complex on the surface of the patients' platelets. Western blotting revealed normal levels of GPIX, decreased levels of GPIb beta and GPV, and < 1% of GPIb alpha. RT-PCR studies showed the presence of mRNA coding for GPIb alpha, GPIb beta, GPIX and GPV. Sequencing showed a three-base deletion which results in the absence of a Leucine Residue, highly conserved across the seven Leucine-rich repeats of GPIb alpha and also within the other members of the Leucine-rich glycoprotein family. The absence of the Leucine 179 in a patient's GPIb alpha is believed to cause a conformational change in the protein which would account for the lack of binding of most of the MoAbs tested and would be responsible for the absence of von Willebrand factor binding. These results point to the Leucine-rich region of GPIb alpha as being required for the correct exposure of the von Willebrand binding site as well as for the correct assembly and stability of the GPIb/IX/V complex on the platelet surface.

  • a three base deletion removing a Leucine Residue in a Leucine rich repeat of platelet glycoprotein ibα associated with a variant of bernard soulier syndrome nancy i
    British Journal of Haematology, 1995
    Co-Authors: Mariejeanne Baas, Franccois Lanza, Agnegs Schwartz, Daniel Hanau, Jerotme Chevalier, Christian Gachet, Marieelisabeth Briquel, Jeanpierre Cazenave
    Abstract:

    : Leucine-rich repeats are conserved structural motifs present in the four components of the human platelet glycoprotein Ib/IX/V complex receptor for the adhesive protein von Willebrand factor. The absence or abnormality of this complex is responsible for Bernard-Soulier disease, an autosomal recessive bleeding disorder. We report a deletion of Leucine 179, located in a highly conserved position of the seventh Leucine-rich repeat of GPIb alpha, found in a variant form of Bernard-Soulier disease (Bernard-Soulier Nancy I). Three affected siblings of a family were characterized by absence of ristocetin-induced platelet agglutination, although ADP aggregation was normal. Flow cytometry studies showed detectable amounts of all four members of the GPIb/IX/V complex on the surface of the patients' platelets. Western blotting revealed normal levels of GPIX, decreased levels of GPIb beta and GPV, and < 1% of GPIb alpha. RT-PCR studies showed the presence of mRNA coding for GPIb alpha, GPIb beta, GPIX and GPV. Sequencing showed a three-base deletion which results in the absence of a Leucine Residue, highly conserved across the seven Leucine-rich repeats of GPIb alpha and also within the other members of the Leucine-rich glycoprotein family. The absence of the Leucine 179 in a patient's GPIb alpha is believed to cause a conformational change in the protein which would account for the lack of binding of most of the MoAbs tested and would be responsible for the absence of von Willebrand factor binding. These results point to the Leucine-rich region of GPIb alpha as being required for the correct exposure of the von Willebrand binding site as well as for the correct assembly and stability of the GPIb/IX/V complex on the platelet surface.

Jeanpaul Di Rago - One of the best experts on this subject based on the ideXlab platform.

  • functional investigation of an universally conserved Leucine Residue in subunit a of atp synthase targeted by the pathogenic m 9176 t g mutation
    Biochimica et Biophysica Acta, 2019
    Co-Authors: Roza Kucharczyk, Alain Dautant, Francois Godard, Deborah Tribouillardtanvier, Jeanpaul Di Rago
    Abstract:

    Abstract Protons are transported from the mitochondrial matrix to the intermembrane space of mitochondria during the transfer of electrons to oxygen and shuttled back to the matrix by the a subunit and a ring of identical c subunits across the membrane domain (FO) of ATP synthase, which is coupled to ATP synthesis. A mutation (m.9176 T > G) of the mitochondrial ATP6 gene that replaces an universally conserved Leucine Residue into arginine at amino acid position 217 of human subunit a (aL217R) has been associated to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) and MILS (Maternally Inherited Leigh's Syndrome) diseases. We previously showed that an equivalent thereof in Saccharomyces cerevisiae (aL237R) severely impairs subunit a assembly/stability and decreases by >90% the rate of mitochondrial ATP synthesis. Herein we identified three spontaneous first-site intragenic suppressors (aR237M, aR237T and aR237S) that fully restore ATP synthase assembly. However, mitochondrial ATP synthesis rate was only partially recovered (40–50% vs wild type yeast). In light of recently described high-resolution yeast ATP synthase structures, the detrimental consequences of the aL237R change can be explained by steric and electrostatic hindrance with the universally conserved subunit a arginine Residue (aR176) that is essential to FO activity. aL237 together with three other nearby hydrophobic Residues have been proposed to prevent ion shortage between two physically separated hydrophilic pockets within the FO. Our results suggest that aL237 favors subunit c-ring rotation by optimizing electrostatic interaction between aR176 and an acidic Residue in subunit c (cE59) known to be essential also to the activity of FO.

Guangyu Wu - One of the best experts on this subject based on the ideXlab platform.

  • a single conserved Leucine Residue on the first intracellular loop regulates er export of g protein coupled receptors
    Traffic, 2009
    Co-Authors: Matthew T Duvernay, Chunmin Dong, Xiaoping Zhang, Melanie Robitaille, Terence E Hebert, Guangyu Wu
    Abstract:

    The intrinsic structural determinants for export trafficking of G protein-coupled receptors (GPCRs) have been mainly identified in the termini of the receptors. In this report, we determined the role of the first intracellular loop (ICL1) in the transport from the endoplasmic reticulum (ER) to the cell surface of GPCRs. The α2B-adrenergic receptor (AR) mutant lacking the ICL1 is unable to traffic to the cell surface and to initiate signaling measured as ERK1/2 activation. Mutagenesis studies identify a single Leu48 Residue in the ICL1 modulates α2B-AR export from the ER. The ER export function of the Leu48 Residue can be substituted by Phe, but not Ile, Val, Tyr and Trp, and is unlikely involved in correct folding or dimerization of α2B-AR in the ER. Importantly, the isolated Leu Residue is remarkably conserved in the center of the ICL1s among the family A GPCRs and is also required for the export to the cell surface of β2-AR, α1B-AR and angiotensin II type 1 receptor. These data indicate a crucial role for a single Leu Residue within the ICL1 in ER export of GPCRs.

  • a single conserved Leucine Residue in the first intracellular loops is required for endoplasmic reticulum export of g protein coupled receptors
    The FASEB Journal, 2008
    Co-Authors: Matthew T Duvernay, Guangyu Wu
    Abstract:

    The intrinsic structural determinants for export trafficking of G protein-coupled receptors (GPCRs) have been mainly identified in the termini of the receptors. In this report, we determined the role of the first intracellular loops (ICL1s) in the transport from the endoplasmic reticulum (ER) to the cell surface of GPCRs. The α2B-adrenergic receptor (AR) mutant lacking the ICL1 is completely unable to traffic to the cell surface and to initiate signaling measured as ERK1/2 activation. Mutagenesis studies identify a single Leu48 Residue in the ICL1 absolutely essential for the export of α2B-AR from the ER. The ER export function of the Leu48 Residue can be substituted by Phe, but not Ile, Val, Tyr and Trp, and is unlikely involved in correct folding or dimerization of α2B-AR in the ER. Importantly, the isolated Leu Residue is remarkably conserved in the center of the ICL1s amongst the family A GPCRs and is also required for the export to the cell surface of β2AR, α1B-AR and angiotensin II type 1 receptor. These data indicate an essential role for a single Leu Residue within the ICL1s in ER export of GPCRs.

Koichi Honda - One of the best experts on this subject based on the ideXlab platform.

  • an increase in the transglycosylation activity of saccharomycopsis α amylase altered by site directed mutagenesis
    Biochimica et Biophysica Acta, 1991
    Co-Authors: Ikuo Matsui, Sakuzo Fukui, Kazuhiko Ishikawa, Sachio Miyairi, Koichi Honda
    Abstract:

    The 84th tryptophan Residue in Saccharomycopsis α-amylase molecule was replaced by a Leucine Residue and the resulting site-directed mutant, W84L enzyme, showed an increase in transglycosylation activity. At a 40% digestion point of maltoheptaose (G7), for example, maltooligosaccharide products larger than maltodecaose (G10) amounted to approx. 60% of the total product from the mutant enzyme reaction, whereas no such large products were observed in the native enzyme reaction. Analysis of the reaction products from p-nitrophenyl maltooligosaccharides indicated that these large products were formed by addition of the hydrolysis products on the nonreducing end side to the starting intact substrates. These results suggest that the tryptophan Residue located at subsite 3 of the enzyme plays an important role not only to hold the substrate, but also to liberate the hydrolysis products from the substrate binding pocket.

Mariejeanne Baas - One of the best experts on this subject based on the ideXlab platform.

  • A three‐base deletion removing a Leucine Residue in a Leucine‐rich repeat of platelet glycoprotein Ibα associated with a variant of Bernard‐Soulier syndrome (Nancy I)
    British Journal of Haematology, 1995
    Co-Authors: Mariejeanne Baas, Franccois Lanza, Agnegs Schwartz, Daniel Hanau, Jerotme Chevalier, Christian Gachet, Marieelisabeth Briquel, Jeanpierre Cazenave
    Abstract:

    : Leucine-rich repeats are conserved structural motifs present in the four components of the human platelet glycoprotein Ib/IX/V complex receptor for the adhesive protein von Willebrand factor. The absence or abnormality of this complex is responsible for Bernard-Soulier disease, an autosomal recessive bleeding disorder. We report a deletion of Leucine 179, located in a highly conserved position of the seventh Leucine-rich repeat of GPIb alpha, found in a variant form of Bernard-Soulier disease (Bernard-Soulier Nancy I). Three affected siblings of a family were characterized by absence of ristocetin-induced platelet agglutination, although ADP aggregation was normal. Flow cytometry studies showed detectable amounts of all four members of the GPIb/IX/V complex on the surface of the patients' platelets. Western blotting revealed normal levels of GPIX, decreased levels of GPIb beta and GPV, and < 1% of GPIb alpha. RT-PCR studies showed the presence of mRNA coding for GPIb alpha, GPIb beta, GPIX and GPV. Sequencing showed a three-base deletion which results in the absence of a Leucine Residue, highly conserved across the seven Leucine-rich repeats of GPIb alpha and also within the other members of the Leucine-rich glycoprotein family. The absence of the Leucine 179 in a patient's GPIb alpha is believed to cause a conformational change in the protein which would account for the lack of binding of most of the MoAbs tested and would be responsible for the absence of von Willebrand factor binding. These results point to the Leucine-rich region of GPIb alpha as being required for the correct exposure of the von Willebrand binding site as well as for the correct assembly and stability of the GPIb/IX/V complex on the platelet surface.

  • a three base deletion removing a Leucine Residue in a Leucine rich repeat of platelet glycoprotein ibα associated with a variant of bernard soulier syndrome nancy i
    British Journal of Haematology, 1995
    Co-Authors: Mariejeanne Baas, Franccois Lanza, Agnegs Schwartz, Daniel Hanau, Jerotme Chevalier, Christian Gachet, Marieelisabeth Briquel, Jeanpierre Cazenave
    Abstract:

    : Leucine-rich repeats are conserved structural motifs present in the four components of the human platelet glycoprotein Ib/IX/V complex receptor for the adhesive protein von Willebrand factor. The absence or abnormality of this complex is responsible for Bernard-Soulier disease, an autosomal recessive bleeding disorder. We report a deletion of Leucine 179, located in a highly conserved position of the seventh Leucine-rich repeat of GPIb alpha, found in a variant form of Bernard-Soulier disease (Bernard-Soulier Nancy I). Three affected siblings of a family were characterized by absence of ristocetin-induced platelet agglutination, although ADP aggregation was normal. Flow cytometry studies showed detectable amounts of all four members of the GPIb/IX/V complex on the surface of the patients' platelets. Western blotting revealed normal levels of GPIX, decreased levels of GPIb beta and GPV, and < 1% of GPIb alpha. RT-PCR studies showed the presence of mRNA coding for GPIb alpha, GPIb beta, GPIX and GPV. Sequencing showed a three-base deletion which results in the absence of a Leucine Residue, highly conserved across the seven Leucine-rich repeats of GPIb alpha and also within the other members of the Leucine-rich glycoprotein family. The absence of the Leucine 179 in a patient's GPIb alpha is believed to cause a conformational change in the protein which would account for the lack of binding of most of the MoAbs tested and would be responsible for the absence of von Willebrand factor binding. These results point to the Leucine-rich region of GPIb alpha as being required for the correct exposure of the von Willebrand binding site as well as for the correct assembly and stability of the GPIb/IX/V complex on the platelet surface.