Etude structure/fonction d'une proteine ABC : SUR, le récepteur des sulfonylurées

Abstract : ATP-sensitive K+ channels (KATP channels) are metabolic sensors formed by the association of an ATP-inhibited inwardly
rectifying K+ channel (Kir6.2) and a regulatory subunit, SUR, of the ABC protein family. SUR adjusts channel gating as a
function of internal ATP and ADP. It is also the target of pharmaceutical KATP channel openers (KCO) or blockers.
We have worked on several structure/function relationships of SUR as a model of eucaryotic ABC protein. The natural
association of SUR with an ion channel greatly facilitates its study as it allows the use of the patch clamp technique.
Pursuing work on the site of action of KCO, we have shown that the molecular selectivity of the SUR isoforms for KCOs
results from the compactness of SUR2A Thr 1253 as opposed to the bulkiness of SUR1 Met1290. This size parameter
appears as the most important criteria for the pharmacological activation of KATP channels.
Our work then focused on a glutamic acid reach domain of SUR (succession of 15 glutamic or aspartic residues).
Extensive mutagenesis of this domain suggested that it is not involved in channel function in our expression system.
We tested the intracellular effects of Zn2+ and Cd2+ on KATP channels and showed that these ions can activate the channels
by binding to SUR. This binding site remains to be determined.
To examine the respective role of each nucleotide binding domain, we have created hybrid SUR2A proteins with
duplicated or switched NBDs (SUR2A NBD1-NBD1, SUR2A NBD2-NBD2 and SUR2A NBD2-NBD1). Beside
demonstrating that these proteins remain functional when co-expressed with Kir6.2, our results suggest that (1) the NBDs
are interchangeable (2) ADP activation requires both NBDs (3) KCOs are effective in the absence of NBD2.
Document type :
Theses
Bioengineering. Université Joseph-Fourier - Grenoble I, 2005. French


https://tel.archives-ouvertes.fr/tel-00011848
Contributor : Fabienne Gally <>
Submitted on : Wednesday, March 8, 2006 - 9:55:25 PM
Last modification on : Wednesday, March 22, 2006 - 3:56:25 PM

Identifiers

  • HAL Id : tel-00011848, version 1

Collections

UJF | CEA | UGA

Citation

Fabienne Gally. Etude structure/fonction d'une proteine ABC : SUR, le récepteur des sulfonylurées. Bioengineering. Université Joseph-Fourier - Grenoble I, 2005. French. <tel-00011848>

Export

Share

Metrics

Consultation de
la notice

174

Téléchargement du document

439