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Article

Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain

1
IMPMC, UMR 7590, CNRS, Muséum National d’Histoire Naturelle, Sorbonne Université, 75005 Paris, France
2
Laboratoire de Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris-Saclay, 4 Ave. des Sciences, 91190 Gif-sur-Yvette, France
3
Institut Pasteur, C2RT-Plate-Forme de Cristallographie CNRS-UMR3528, 75724 Paris, France
4
CNRS, IBS, CEA, University Grenoble Alpes, 38044 Grenoble, France
5
CNRS UMR7370, LP2M, Labex ICST, Faculté de Médecine, University Côte d’Azur, 06560 Nice, France
6
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgeri 1, 34127 Trieste, Italy
*
Author to whom correspondence should be addressed.
Academic Editors: Alberto Spisni, Ian A. Nicholls and Vladimir N. Uversky
Int. J. Mol. Sci. 2022, 23(1), 335; https://doi.org/10.3390/ijms23010335
Received: 16 November 2021 / Revised: 18 December 2021 / Accepted: 23 December 2021 / Published: 29 December 2021
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
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. View Full-Text
Keywords: crystal structure of KirBac3.1 W46R; HDX-mass spectrometry; molecular dynamics; normal modes; electrophysiology; gain of function Kir; neonatal diabetes mellitus crystal structure of KirBac3.1 W46R; HDX-mass spectrometry; molecular dynamics; normal modes; electrophysiology; gain of function Kir; neonatal diabetes mellitus
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MDPI and ACS Style

Fagnen, C.; Bannwarth, L.; Oubella, I.; Zuniga, D.; Haouz, A.; Forest, E.; Scala, R.; Bendahhou, S.; De Zorzi, R.; Perahia, D.; Vénien-Bryan, C. Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain. Int. J. Mol. Sci. 2022, 23, 335. https://doi.org/10.3390/ijms23010335

AMA Style

Fagnen C, Bannwarth L, Oubella I, Zuniga D, Haouz A, Forest E, Scala R, Bendahhou S, De Zorzi R, Perahia D, Vénien-Bryan C. Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain. International Journal of Molecular Sciences. 2022; 23(1):335. https://doi.org/10.3390/ijms23010335

Chicago/Turabian Style

Fagnen, Charline, Ludovic Bannwarth, Iman Oubella, Dania Zuniga, Ahmed Haouz, Eric Forest, Rosa Scala, Saïd Bendahhou, Rita De Zorzi, David Perahia, and Catherine Vénien-Bryan. 2022. "Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain" International Journal of Molecular Sciences 23, no. 1: 335. https://doi.org/10.3390/ijms23010335

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