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Cited by 51Ion Channels and ReceptorsProtein Structure and DynamicsIon channel regulation and function

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Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity

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Goretzki, Benedikt, Wiedemann, Christoph, McCray, Brett A., Schäfer, Stefan L., Jansen, Jasmin, Tebbe, Frederike, Mitrovic, Sarah-Ana, Nöth, Julia, Cabezudo, Ainara Claveras, Donohue, Jack K., Jeffries, Cy M., Steinchen, Wieland, Stengel, Florian, Sumner, Charlotte J., Hummer, Gerhard, Hellmich, Ute A.·2023·Nature Communications
DOI 10.1038/s41467-023-39808-4PMC PMC10344929

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Abstract

Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and the network of antagonistic regulatory elements it encodes. These modulate channel activity in a hierarchical lipid-dependent manner through transient long-range interactions. A highly conserved autoinhibitory patch acts as a master regulator by competing with PIP 2 binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP 2 -binding site and the membrane reduces the force exerted by the IDR on the structured core of TRPV4. This work demonstrates that IDR structural dynamics are coupled to TRPV4 activity and highlights the importance of IDRs for TRP channel function and regulation.

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Metadata

Authors
Goretzki, B., Wiedemann, C., McCray, B. A., Schäfer, S. L., Jansen, J., Tebbe, F., Mitrovic, S.-A., Nöth, J., Cabezudo, A. C., Donohue, J. K., Jeffries, C. M., Steinchen, W., Stengel, F., Sumner, C. J., Hummer, G., & Hellmich, U. A.
Affiliations
  • Goethe University Frankfurt (DE)
  • Friedrich Schiller University Jena (DE)
  • Johns Hopkins University (US)
  • University of Konstanz (DE)
  • Johannes Gutenberg University Mainz (DE)
  • Max Planck Institute of Biophysics (DE)
  • European Molecular Biology Laboratory (DE)
  • Philipps University of Marburg (DE)
Corresponding author
Hellmich, Ute A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-07-13
Volume
14
Issue
1
Pages
4165-4165
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-39808-4
PMC
PMC10344929
OpenAlex
W4384200955
Cited by
51
References
3
Citations by year
2026: 13 · 2025: 19 · 2024: 13 · 2023: 6
FWCI
9.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KOPS (University of Konstanz) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Common Library Network (Der Gemeinsame Bibliotheksverbund) (submittedVersion, cc-by)
Funders
  • Muscular Dystrophy Association (629305)
  • European Commission
  • Deutsche Forschungsgemeinschaft (EXC 2051—, STE 2517/5-1, 390713860, 450648163, 324652314)
  • Max-Planck-Gesellschaft
  • National Institutes of Health
  • Deutsches Elektronen-Synchrotron (SAXS-1106)
  • European Regional Development Fund
  • National Institute of Neurological Disorders and Stroke (K08NS102509, NS102509, R35NS122306)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
TRPV4, intrinsically disordered regions, PIP2 binding, long-range interactions, structural ensembles, molecular dynamics simulation, channel deactivation
MeSH terms
Protein Domains, Cell Physiological Phenomena, Lipids, Regulatory Sequences, Nucleic Acid, TRPV Cation Channels

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