Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 50, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2210669119
Keywords
ligand-gated ion channel; Cys-loop receptors; small-angle neutron scattering; calcium
Categories
Funding
- Swedish Foundation for Strategic Research through the SwedNess graduate school [GSn15-0008]
- Knut and Alice Wallenberg Foundation
- Swedish Research Council [2019-02433, 2021-05806]
- Erasmus plus program
- Swedish e-Science Research Centre
- BioExcel Center of Excellence [EU-823830]
- Erling Persson Foundation
- Kempe Foundation
- Swedish Research Council [2019-02433, 2021-05806] Funding Source: Swedish Research Council
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This study characterized the structure and dynamics of DeCLIC using cryo-EM, SANS, and MD simulations, revealing alternative conformations of the NTD and calcium-binding site and expanding the conformational landscape of the pLGIC family. Moreover, it demonstrated the power of combining low-resolution scattering, high-resolution structural, and MD simulation data to elucidate highly conserved interfacial interactions in the pLGIC family.
Pentameric ligand-gated ion channels (pLGICs) perform electrochemical signal transduction in organisms ranging from bacteria to humans. Among the prokaryotic pLGICs, there is architectural diversity involving N-terminal domains (NTDs) not found in eukaryotic relatives, exemplified by the calcium-sensitive channel (DeCLIC) from a Desulfofustis deltaproteobacterium, which has an NTD in addition to the canonical pLGIC structure. Here, we have characterized the structure and dynamics of DeCLIC through cryoelectron microscopy (cryo-EM), small-angle neutron scattering (SANS), and molecular dynamics (MD) simulations. In the presence and absence of calcium, cryo-EM yielded structures with alternative conformations of the calcium-binding site. SANS profiles further revealed conformational diversity at room temperature beyond that observed in static structures, shown through MD to be largely attributable to rigid-body motions of the NTD relative to the protein core, with expanded and asymmetric conformations improving the fit of the SANS data. This work reveals the range of motion available to the DeCLIC NTD and calcium-binding site, expanding the conformational landscape of the pLGIC family. Further, these findings demonstrate the power of combining low-resolution scattering, high-resolution structural, and MD simulation data to elucidate interfacial interactions that are highly conserved in the pLGIC family.
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