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Titolo:
Probing ligand-induced conformational changes of human CD38
Autore:
Berthelier, V; Laboureau, J; Boulla, G; Schuber, F; Deterre, P;
Indirizzi:
Hop La Pitie Salpetriere, Grp Hosp Pitie Salpetriere, Lab Immunol Cellulaire, CNRS,UMR 7627, F-75651 Paris 13, France Hop La Pitie Salpetriere Paris France 13 7627, F-75651 Paris 13, France Univ Strasbourg 1, Fac Pharm, Chim Bioorgan Lab, CNRS,UMR 7514, Strasbourg, France Univ Strasbourg 1 Strasbourg France , CNRS,UMR 7514, Strasbourg, France
Titolo Testata:
EUROPEAN JOURNAL OF BIOCHEMISTRY
fascicolo: 10, volume: 267, anno: 2000,
pagine: 3056 - 3064
SICI:
0014-2956(200005)267:10<3056:PLCCOH>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYCLIC ADP-RIBOSE; ADENINE-DINUCLEOTIDE GLYCOHYDROLASE; TRANSMEMBRANE GLYCOPROTEIN CD38; LYMPHOCYTE ANTIGEN CD38; T-CELLS; LIMITED PROTEOLYSIS; NAD+ GLYCOHYDROLASE; HUMAN ERYTHROCYTES; CARBOXYL-TERMINUS; SELF-AGGREGATION;
Keywords:
ecto-enzyme; inactivation; proteolysis; cysteine; NAD;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Deterre, P Hop La Pitie Salpetriere, Grp Hosp Pitie Salpetriere, Lab Immunol Cellulaire, CNRS,UMR 7627, Bat CERVI,83 Blvd Hop, F-75651 Paris 13, France Hop La Pitie Salpetriere Bat CERVI,83 Blvd Hop Paris France 13
Citazione:
V. Berthelier et al., "Probing ligand-induced conformational changes of human CD38", EUR J BIOCH, 267(10), 2000, pp. 3056-3064

Abstract

The lymphoid surface antigen CD38 is basically a NAD(+)glycohydrolase, which is also involved in the metabolism of cyclic ADP-ribose. Besides, this ecto-enzyme has potential signalling roles in T- and B-cells. Such multiple functions prompted us to study the molecular dynamics of the CD38 protein and especially the relationship between its ecto-enzymatic active site and its epitope, i.e. the binding site of most known anti-CD38 monoclonal antibodies. Both epitopic and enzymatic sites were shown to be degraded by proteases, such as trypsin or chymotrypsin. This sensitivity was almost entirely suppressed in the presence of substrates or inhibitors. Both sites were also degraded in the presence of reducing agents, as dithiothreitol. Inhibitory ligands induced the same resistance of both sites against reducing attack. The binding of CD38 ligands to the active site triggers therefore conformational changes that shield some backbone bonds and disulfide bridges against, respectively, proteolytic cleavage or reduction. This transconformationwas found moreover to irreversibly take place after incubation with substrates such as NAD(+) in the presence of dithiothreitol. The epitope remainedpreserved, while the enzymatic activity was lost. This inactivation probably resulted from the covalent trapping of the catalytically reactive intermediate in the active site (i.e. paracatalytic inactivation). These data have major implications in the knowledge of the CD38 structure, especially with regard to the location of disulfide bridges and their accessibility. Potential consequences of the conformational plasticity of CD38 should also be considered in its physiological functions such as signalling.

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Documento generato il 24/11/20 alle ore 07:11:22