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PreprintCited by 31Ion channel regulation and functionProtein Structure and DynamicsIon Transport and Channel Regulation

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Structures of Tweety Homolog Proteins TTYH2 and TTYH3 reveal a Ca 2+ -dependent switch from intra- to inter-membrane dimerization

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Li, Baobin, Hoel, Christopher M., Brohawn, Stephen G.·2021·Nature Communications
DOI 10.1101/2021.08.15.456437PMC PMC8617170

Preprint — published as 10.1038/s41467-021-27283-8 · Paper page

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Abstract

Tweety homologs (TTYHs) comprise a conserved family of transmembrane proteins found in eukaryotes with three members (TTYH1-3) in vertebrates. They are widely expressed in mammals including at high levels in the nervous system and have been implicated in cancers and other diseases including epilepsy, chronic pain, and viral infections. TTYHs have been reported to form Ca 2+ - and cell volume-regulated anion channels structurally distinct from any characterized protein family with potential roles in cell adhesion, migration, and developmental signaling. To provide insight into TTYH family structure and function, we determined cryo-EM structures of Mus musculus TTYH2 and TTYH3 in lipid nanodiscs. TTYH2 and TTYH3 adopt a novel fold which includes an extended extracellular domain with a partially solvent exposed pocket that may be an interaction site for hydrophobic molecules. In the presence of Ca 2+ , TTYH2 and TTYH3 form homomeric cis-dimers bridged by extracellularly coordinated Ca 2+ . Strikingly, in the absence of Ca 2+ , TTYH2 forms trans-dimers that span opposing membranes across a ~130 Å intermembrane space as well as a monomeric state. All TTYH structures lack ion conducting pathways and we do not observe TTYH2-dependent channel activity in cells. We conclude TTYHs are not pore forming subunits of anion channels and their function may involve Ca 2+ -dependent changes in quaternary structure, interactions with hydrophobic molecules near the extracellular membrane surface, and/or association with additional protein partners.

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Metadata

Authors
Li, B., Hoel, C. M., & Brohawn, S. G.
Affiliations
QB3 (US)
Corresponding author
Brohawn, Stephen G.
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2021-08-16
Volume
12
Issue
1
Pages
6913-6913
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2021.08.15.456437
PMC
PMC8617170
OpenAlex
W3214833894
Cited by
31
References
1
Citations by year
2026: 7 · 2025: 4 · 2024: 9 · 2023: 2 · 2022: 9
FWCI
1.57
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health and Human Services (GM123496)
  • McKnight Endowment Fund for Neuroscience
  • Alfred P. Sloan Foundation
  • New York Stem Cell Foundation (NYSCF-R-N145)
  • McKnight Foundation
  • National Institute of General Medical Sciences (GM123496, DP2GM123496)
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 › Molecular Biology › Ion Transport and Channel Regulation
Keywords
transmembrane proteins, protein structure, lipid nanodiscs, extracellular domain, anion channels, quaternary structure, Mus musculus
MeSH terms
Anoctamins, Animals, Biological Transport, Calcium, Cell Adhesion, Membrane Proteins, Signal Transduction, Chloride Channels, Dimerization, Cryoelectron Microscopy, Receptor, EphB2, Cell Size, Mice, Eukaryota, Hydrophobic and Hydrophilic Interactions, Chronic Pain

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