Cryo-electron microscopy unveils unique structural features of the human Kir2.1 channel.

Autor: Fernandes CAH; UMR 7590, CNRS, Muséum National d'Histoire Naturelle, IRD, Institut de Minéralogie, Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005 Paris, France., Zuniga D; UMR 7590, CNRS, Muséum National d'Histoire Naturelle, IRD, Institut de Minéralogie, Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005 Paris, France., Fagnen C; UMR 7590, CNRS, Muséum National d'Histoire Naturelle, IRD, Institut de Minéralogie, Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005 Paris, France., Kugler V; IMPReSs Facility, Biotechnology and Cell Signaling UMR 7242, CNRS-University of Strasbourg, Illkirch, Cedex, France., Scala R; CNRS UMR7370, LP2M, Labex ICST, Faculté de Médecine, Université Côte d'Azur, Nice, France., Péhau-Arnaudet G; Ultrastructural BioImaging Core Facility/UMR 3528, Institut Pasteur, 75724 Paris Cedex 15, France., Wagner R; IMPReSs Facility, Biotechnology and Cell Signaling UMR 7242, CNRS-University of Strasbourg, Illkirch, Cedex, France., Perahia D; Laboratoire de Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris-Saclay, 4 Ave. des Sciences, 91190 Gif-sur-Yvette, France., Bendahhou S; CNRS UMR7370, LP2M, Labex ICST, Faculté de Médecine, Université Côte d'Azur, Nice, France., Vénien-Bryan C; UMR 7590, CNRS, Muséum National d'Histoire Naturelle, IRD, Institut de Minéralogie, Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005 Paris, France.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2022 Sep 23; Vol. 8 (38), pp. eabq8489. Date of Electronic Publication: 2022 Sep 23.
DOI: 10.1126/sciadv.abq8489
Abstrakt: We present the first structure of the human Kir2.1 channel containing both transmembrane domain (TMD) and cytoplasmic domain (CTD). Kir2.1 channels are strongly inward-rectifying potassium channels that play a key role in maintaining resting membrane potential. Their gating is modulated by phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Genetically inherited defects in Kir2.1 channels are responsible for several rare human diseases, including Andersen's syndrome. The structural analysis (cryo-electron microscopy), surface plasmon resonance, and electrophysiological experiments revealed a well-connected network of interactions between the PIP 2 -binding site and the G-loop through residues R312 and H221. In addition, molecular dynamics simulations and normal mode analysis showed the intrinsic tendency of the CTD to tether to the TMD and a movement of the secondary anionic binding site to the membrane even without PIP 2 . Our results revealed structural features unique to human Kir2.1 and provided insights into the connection between G-loop and gating and the pathological mechanisms associated with this channel.
Databáze: MEDLINE
Externí odkaz: