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  1. Thesis ; Online: Structure and modulation of the rod cyclic nucleotide-gated ion channel

    Barret, Diane C.A.

    2022  

    Abstract: Vertebrate cyclic nucleotide-gated (CNG) channels are non-selective cation channels. They play an essential role in the signal transduction of visual and olfactory sensory systems. There, CNG channels close in response to the decrease of cyclic ... ...

    Abstract Vertebrate cyclic nucleotide-gated (CNG) channels are non-selective cation channels. They play an essential role in the signal transduction of visual and olfactory sensory systems. There, CNG channels close in response to the decrease of cyclic nucleotide concentration, inducing the hyperpolarisation of the plasma membrane. In rod and cone photoreceptors, their role is crucial for the control of intracellular calcium concentration and the capability of the photoreceptors to respond to light stimuli. CNG channels mutations have been identified in patients affected by retinitis pigmentosa and achromatopsia, two common disabling vision diseases for which no cure is currently available. Discovered in the mid-80s, CNG channels have since been extensively studied. However, CNG channels have been notoriously dicult targets for structural biology, in part due to their particular subunit composition and stoichiometry. My PhD project focused on producing the first structure of a heteromeric CNG channel. In the first part of my work, I solved the structure in the closed (apo) state of the rod CNG channel (CNGA1/B1) purified from bovine retinas to 3.5 Å resolution. This allowed identifying new structural features on the regulatory CNGB1 subunit not present in homomeric CNGA channels. These include a new gate within the ion conduction pathway, that we called “CNGB gate”. This gate is composed of a single residue (R994) on the CNGB1 subunit that reaches into the ionic pathway. While this residue is conserved among all CNGB1 subunits, it is replaced by glutamine in the CNGB3 subunit (present in the cones CNG channels) in some species. I have identified one helix in the CNGB1 subunit that was not previously described. We called this helix the “D-helix”. In the second part of my work, I present how this new structural feature is involved in the CNG channel/calmodulin interaction. During the four years of my thesis, other research groups have produced structures of the rod and cone CNG channels – the human rod CNG channel ...
    Keywords CNG channel ; Cryo-EM ; Calmodulin ; Structure ; Vision ; info:eu-repo/classification/ddc/570 ; Life sciences
    Subject code 572
    Language English
    Publisher ETH Zurich
    Publishing country ch
    Document type Thesis ; Online
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  2. Article ; Online: The structure of cyclic nucleotide-gated channels in rod and cone photoreceptors.

    Barret, Diane C A / Kaupp, U Benjamin / Marino, Jacopo

    Trends in neurosciences

    2022  Volume 45, Issue 10, Page(s) 763–776

    Abstract: Cyclic nucleotide-gated (CNG) channels play a central role in rod and cone photoreceptors of the vertebrate retina. In photoreceptors, light triggers a series of biochemical reactions that ultimately close CNG channels and evoke a brief voltage pulse, a ... ...

    Abstract Cyclic nucleotide-gated (CNG) channels play a central role in rod and cone photoreceptors of the vertebrate retina. In photoreceptors, light triggers a series of biochemical reactions that ultimately close CNG channels and evoke a brief voltage pulse, a signal that is later passed on to the brain. Malfunction of CNG channels can lead to loss of vision. Thus, understanding their function in atomic and mechanistic detail is important. Because of the complex subunit stoichiometry of these channels, elucidation of their structure has proved challenging. Recently, several cryoelectron microscopy (EM) structures of rod and cone CNG channels revealed unexpected structural features. We compare these structures side by side and highlight similarities and differences in key structural elements. We discuss the implications of the channels' structure for questions about their gating, ion permeation, and modulation. These results inform new strategies to further characterize the structural basis of CNG channels functioning in rods and cones.
    MeSH term(s) Cryoelectron Microscopy ; Cyclic Nucleotide-Gated Cation Channels ; Humans ; Nucleotides, Cyclic ; Retina ; Retinal Cone Photoreceptor Cells/physiology
    Chemical Substances Cyclic Nucleotide-Gated Cation Channels ; Nucleotides, Cyclic
    Language English
    Publishing date 2022-08-05
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 282488-7
    ISSN 1878-108X ; 0378-5912 ; 0166-2236
    ISSN (online) 1878-108X
    ISSN 0378-5912 ; 0166-2236
    DOI 10.1016/j.tins.2022.07.001
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  3. Article ; Online: The structure of the native CNGA1/CNGB1 CNG channel from bovine retinal rods.

    Barret, Diane C A / Schertler, Gebhard F X / Kaupp, U Benjamin / Marino, Jacopo

    Nature structural & molecular biology

    2021  Volume 29, Issue 1, Page(s) 32–39

    Abstract: In rod photoreceptors of the retina, the cyclic nucleotide-gated (CNG) channel is composed of three CNGA and one CNGB subunits, and it closes in response to light activation to generate an electrical signal that is conveyed to the brain. Here we report ... ...

    Abstract In rod photoreceptors of the retina, the cyclic nucleotide-gated (CNG) channel is composed of three CNGA and one CNGB subunits, and it closes in response to light activation to generate an electrical signal that is conveyed to the brain. Here we report the cryo-EM structure of the closed state of the native rod CNG channel isolated from bovine retina. The structure reveals differences between CNGA1 and CNGB1 subunits. Three CNGA1 subunits are tethered at their C terminus by a coiled-coil region. The C-helix in the cyclic nucleotide-binding domain of CNGB1 features a different orientation from that in the three CNGA1 subunits. The arginine residue R994 of CNGB1 reaches into the ionic pathway and blocks the pore, thus introducing an additional gate, which is different from the central hydrophobic gate known from homomeric CNGA channels. These results address the long-standing question of how CNGB1 subunits contribute to the function of CNG channels in visual and olfactory neurons.
    MeSH term(s) Amino Acid Sequence ; Animals ; Cattle ; Conserved Sequence ; Cyclic Nucleotide-Gated Cation Channels/chemistry ; Cyclic Nucleotide-Gated Cation Channels/ultrastructure ; Models, Molecular ; Protein Subunits/chemistry ; Protein Subunits/metabolism ; Retinal Rod Photoreceptor Cells/metabolism ; Retinal Rod Photoreceptor Cells/ultrastructure
    Chemical Substances Cyclic Nucleotide-Gated Cation Channels ; Protein Subunits
    Language English
    Publishing date 2021-12-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-021-00700-8
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    Zs.A 4101: Show issues Location:
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  4. Article ; Online: Structural basis of the partially open central gate in the human CNGA1/CNGB1 channel explained by additional density for calmodulin in cryo-EM map.

    Barret, Diane C A / Schertler, Gebhard F X / Kaupp, U Benjamin / Marino, Jacopo

    Journal of structural biology

    2021  Volume 214, Issue 1, Page(s) 107828

    Abstract: The recently reported structure of the human CNGA1/CNGB1 CNG channel in the open state (Xue et al., 2021a) shows that one CNGA1 and one CNGB1 subunit do not open the central hydrophobic gate completely upon cGMP binding. This is different from what has ... ...

    Abstract The recently reported structure of the human CNGA1/CNGB1 CNG channel in the open state (Xue et al., 2021a) shows that one CNGA1 and one CNGB1 subunit do not open the central hydrophobic gate completely upon cGMP binding. This is different from what has been reported for CNGA homomeric channels (Xue et al., 2021b; Zheng et al., 2020). In seeking to understand how this difference is due to the presence of the CNGB1 subunit, we find that the deposited density map (Xue et al., 2021a) (EMDB 24465) contains an additional density not reported in the images of the original publication. This additional density fits well the structure of calmodulin (CaM), and it unambiguously connects the newly identified D-helix of CNGB1 to one of the CNGA1 helices (A1
    MeSH term(s) Binding Sites ; Calmodulin/metabolism ; Cryoelectron Microscopy ; Cyclic Nucleotide-Gated Cation Channels/chemistry ; Cyclic Nucleotide-Gated Cation Channels/metabolism ; Humans ; Retinal Rod Photoreceptor Cells/metabolism
    Chemical Substances CNGA1 protein, human ; CNGB1 protein, human ; Calmodulin ; Cyclic Nucleotide-Gated Cation Channels
    Language English
    Publishing date 2021-12-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1032718-6
    ISSN 1095-8657 ; 1047-8477
    ISSN (online) 1095-8657
    ISSN 1047-8477
    DOI 10.1016/j.jsb.2021.107828
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    Zs.A 1428: Show issues Location:
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  5. Article ; Online: Structural basis of calmodulin modulation of the rod cyclic nucleotide-gated channel.

    Barret, Diane C A / Schuster, Dina / Rodrigues, Matthew J / Leitner, Alexander / Picotti, Paola / Schertler, Gebhard F X / Kaupp, U Benjamin / Korkhov, Volodymyr M / Marino, Jacopo

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 15, Page(s) e2300309120

    Abstract: Calmodulin (CaM) regulates many ion channels to control calcium entry into cells, and mutations that alter this interaction are linked to fatal diseases. The structural basis of CaM regulation remains largely unexplored. In retinal photoreceptors, CaM ... ...

    Abstract Calmodulin (CaM) regulates many ion channels to control calcium entry into cells, and mutations that alter this interaction are linked to fatal diseases. The structural basis of CaM regulation remains largely unexplored. In retinal photoreceptors, CaM binds to the CNGB subunit of cyclic nucleotide-gated (CNG) channels and, thereby, adjusts the channel's Cyclic guanosine monophosphate (cGMP) sensitivity in response to changes in ambient light conditions. Here, we provide the structural characterization for CaM regulation of a CNG channel by using a combination of single-particle cryo-electron microscopy and structural proteomics. CaM connects the CNGA and CNGB subunits, resulting in structural changes both in the cytosolic and transmembrane regions of the channel. Cross-linking and limited proteolysis-coupled mass spectrometry mapped the conformational changes induced by CaM in vitro and in the native membrane. We propose that CaM is a constitutive subunit of the rod channel to ensure high sensitivity in dim light. Our mass spectrometry-based approach is generally relevant for studying the effect of CaM on ion channels in tissues of medical interest, where only minute quantities are available.
    MeSH term(s) Cyclic Nucleotide-Gated Cation Channels/genetics ; Cyclic Nucleotide-Gated Cation Channels/metabolism ; Calmodulin/metabolism ; Ion Channel Gating/physiology ; Cryoelectron Microscopy ; Calcium/metabolism ; Nucleotides, Cyclic/pharmacology ; Cyclic GMP/metabolism
    Chemical Substances Cyclic Nucleotide-Gated Cation Channels ; Calmodulin ; Calcium (SY7Q814VUP) ; Nucleotides, Cyclic ; Cyclic GMP (H2D2X058MU)
    Language English
    Publishing date 2023-04-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2300309120
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    Zs.A 1148: Show issues Location:
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  6. Article ; Online: Structural basis of calmodulin modulation of the rod cyclic nucleotide-gated channel

    Barret, Diane C.A. / Schuster, Dina / id_orcid:0 000-0001-6611-8237 / Rodrigues, Matthew J. / Leitner, Alexander / Picotti, Paola / Schertler, Gebhard F.X. / Kaupp, U. Benjamin / Korkhov, Volodymyr M. / Marino, Jacopo

    Proceedings of the National Academy of Sciences of the United States of America, 120 (15)

    2023  

    Abstract: Calmodulin (CaM) regulates many ion channels to control calcium entry into cells, and mutations that alter this interaction are linked to fatal diseases. The structural basis of CaM regulation remains largely unexplored. In retinal photoreceptors, CaM ... ...

    Abstract Calmodulin (CaM) regulates many ion channels to control calcium entry into cells, and mutations that alter this interaction are linked to fatal diseases. The structural basis of CaM regulation remains largely unexplored. In retinal photoreceptors, CaM binds to the CNGB subunit of cyclic nucleotide-gated (CNG) channels and, thereby, adjusts the channel's Cyclic guanosine monophosphate (cGMP) sensitivity in response to changes in ambient light conditions. Here, we provide the structural characterization for CaM regulation of a CNG channel by using a combination of single-particle cryo-electron microscopy and structural proteomics. CaM connects the CNGA and CNGB subunits, resulting in structural changes both in the cytosolic and transmembrane regions of the channel. Cross-linking and limited proteolysis-coupled mass spectrometry mapped the conformational changes induced by CaM in vitro and in the native membrane. We propose that CaM is a constitutive subunit of the rod channel to ensure high sensitivity in dim light. Our mass spectrometry-based approach is generally relevant for studying the effect of CaM on ion channels in tissues of medical interest, where only minute quantities are available.

    ISSN:0027-8424

    ISSN:1091-6490
    Keywords ion channel ; structural biology ; cryo-EM ; proteomics ; calmodulin
    Subject code 572
    Language English
    Publishing date 2023-04-11
    Publisher National Academy of Sciences
    Publishing country ch
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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