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

  • Sci Adv. 2022 Sep 23;8(38):eabq8489. doi: 10.1126/sciadv.abq8489.
Carlos A H Fernandes  1 ,  Dania Zuniga  1 ,  Charline Fagnen  1 ,  Valérie Kugler  2 ,  Rosa Scala  3 ,  Gérard Péhau-Arnaudet  4 ,  Renaud Wagner  2 ,  David Perahia  5 ,  Saïd Bendahhou  3 ,  Catherine Vénien-Bryan  1
Affiliations
  • 1. UMR 7590, CNRS, Muséum National d'Histoire Naturelle, IRD, Institut de Minéralogie, Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, 75005 Paris, France.
  • 2. IMPReSs Facility, Biotechnology and Cell Signaling UMR 7242, CNRS-University of Strasbourg, Illkirch, Cedex, France.
  • 3. CNRS UMR7370, LP2M, Labex ICST, Faculté de Médecine, Université Côte d'Azur, Nice, France.
  • 4. Ultrastructural BioImaging Core Facility/UMR 3528, Institut Pasteur, 75724 Paris Cedex 15, France.
  • 5. Laboratoire de Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris-Saclay, 4 Ave. des Sciences, 91190 Gif-sur-Yvette, France.
PMID: 36149965 DOI: 10.1126/sciadv.abq8489
Abstract

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 (PIP2). 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 PIP2-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 PIP2. 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.