Cryo–electron microscopy unveils unique structural features of the human Kir2.1 channel - Sorbonne Université Access content directly
Journal Articles Science Advances Year : 2022

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

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 (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.
Fichier principal
Vignette du fichier
sciadv.abq8489.pdf (7.29 Mo) Télécharger le fichier
Origin Publisher files allowed on an open archive
Licence

Dates and versions

hal-03946508 , version 1 (19-01-2023)

Licence

Identifiers

Cite

Carlos Fernandes, Dania Zuniga, Charline Fagnen, Valérie Kugler, Rosa Scala, et al.. Cryo–electron microscopy unveils unique structural features of the human Kir2.1 channel. Science Advances , 2022, 8 (38), ⟨10.1126/sciadv.abq8489⟩. ⟨hal-03946508⟩
28 View
39 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More