• Orbit mini

    Simultaneous recording from four lipid bilayers

2022 - Cryo–electron microscopy unveils unique structural features of the human Kir2.1 channel

Icon Orbit Mini  Orbit Mini Publication in Science Advances (2022)

Fernandes C., Zuniga D., Fagnen C., Kugler V., Scala R., Péhau-Arnaudet G., Wagner R., Perahia D., Bendahhou S., Vénien-Bryan C.

Orbit Mini Publication in Science Advances (2022) doi:10.1126/sciadv.abq8489


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.

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