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- Title
Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain.
- Authors
Fagnen, Charline; Bannwarth, Ludovic; Oubella, Iman; Zuniga, Dania; Haouz, Ahmed; Forest, Eric; Scala, Rosa; Bendahhou, Saïd; De Zorzi, Rita; Perahia, David; Vénien-Bryan, Catherine
- Abstract
ATP-sensitive potassium (K-ATP) channels are ubiquitously expressed on the plasma membrane of cells in several organs, including the heart, pancreas, and brain, and they govern a wide range of physiological processes. In pancreatic β-cells, K-ATP channels composed of Kir6.2 and SUR1 play a key role in coupling blood glucose and insulin secretion. A tryptophan residue located at the cytosolic end of the transmembrane helix is highly conserved in eukaryote and prokaryote Kir channels. Any mutation on this amino acid causes a gain of function and neonatal diabetes mellitus. In this study, we have investigated the effect of mutation on this highly conserved residue on a KirBac channel (prokaryotic homolog of mammalian Kir6.2). We provide the crystal structure of the mutant KirBac3.1 W46R (equivalent to W68R in Kir6.2) and its conformational flexibility properties using HDX-MS. In addition, the detailed dynamical view of the mutant during the gating was investigated using the in silico method. Finally, functional assays have been performed. A comparison of important structural determinants for the gating mechanism between the wild type KirBac and the mutant W46R suggests interesting structural and dynamical clues and a mechanism of action of the mutation that leads to the gain of function.
- Subjects
TRYPTOPHAN; POTASSIUM channels; BLOOD sugar; CELL membranes; PLASMA cells; CRYSTAL structure
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 1, p335
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23010335