Conformational motions and ligand-binding underlying gating and regulation in IP3R channel

Guizhen Fan, Mariah R. Baker, Lara E. Terry, Vikas Arige, Muyuan Chen, Alexander B. Seryshev, Matthew L. Baker, Steven J. Ludtke, David I. Yule () and Irina I. Serysheva ()
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Guizhen Fan: McGovern Medical School at The University of Texas Health Science Center at Houston
Mariah R. Baker: McGovern Medical School at The University of Texas Health Science Center at Houston
Lara E. Terry: University of Rochester
Vikas Arige: University of Rochester
Muyuan Chen: Baylor College of Medicine
Alexander B. Seryshev: McGovern Medical School at The University of Texas Health Science Center at Houston
Matthew L. Baker: McGovern Medical School at The University of Texas Health Science Center at Houston
Steven J. Ludtke: Baylor College of Medicine
David I. Yule: University of Rochester
Irina I. Serysheva: McGovern Medical School at The University of Texas Health Science Center at Houston

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Inositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca2+ and ATP, revealing conformational changes that couple ligand-binding to channel opening. Using a deep-learning approach and 3D variability analysis we extracted molecular motions of the key protein domains from cryo-EM density data. We find that IP3 binding relies upon intrinsic flexibility of the ARM2 domain in the tetrameric channel. Our results highlight a key role of dynamic side chains in regulating gating behavior of IP3R channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel.

Date: 2022
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DOI: 10.1038/s41467-022-34574-1

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