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Cited by 52Ion channel regulation and functionProtein Structure and DynamicsCalcium signaling and nucleotide metabolism

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

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Fan, Guizhen, Baker, Mariah R., Terry, Lara E., Arige, Vikas, Chen, Muyuan, Seryshev, Alexander B., Baker, Matthew L., Ludtke, Steven J., Yule, David I., Serysheva, Irina I.·2022·Nature Communications
DOI 10.1038/s41467-022-34574-1PMC PMC9663519

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Abstract

Inositol-1,4,5-trisphosphate receptors (IP 3 Rs) are activated by IP 3 and Ca 2+ 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 IP 3 R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP 3 , Ca 2+ 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 IP 3 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 IP 3 R channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel.

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Metadata

Authors
Fan, G., Baker, M. R., Terry, L. E., Arige, V., Chen, M., Seryshev, A. B., Baker, M. L., Ludtke, S. J., Yule, D. I., & Serysheva, I. I.
Affiliations
  • The University of Texas Health Science Center at Houston (US)
  • University of Rochester Medicine (US)
  • Baylor College of Medicine (US)
Corresponding author
  • Yule, David I.
  • Serysheva, Irina I.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-14
Volume
13
Issue
1
Pages
6942-6942
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34574-1
PMC
PMC9663519
OpenAlex
W4308963932
Cited by
52
References
1
Citations by year
2026: 10 · 2025: 12 · 2024: 11 · 2023: 18 · 2022: 1
FWCI
3.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01GM072804, R01GM080139)
  • U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (DE019245)
  • American Heart Association (18CDA34110086)
  • Welch Foundation (AU-2014-20190330, AU-2014-20220331)
  • Cancer Prevention and Research Institute of Texas (RP190602)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
IP3 receptor, IP3R1, channel gating, ligand binding, conformational dynamics, IP3 binding, calcium binding, ATP binding, nanodisc reconstitution, deep learning, intracellular calcium signaling, ion channel structure
MeSH terms
Protein Domains, Calcium, Ligands, Inositol 1,4,5-Trisphosphate, Calcium Signaling, Inositol 1,4,5-Trisphosphate Receptors

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