Structural insights into the activation mechanism of the human zinc-activated channel
Abstract The zinc-activated channel (ZAC) is an atypical mammalian cys-loop receptor (CLR) that is activated by zinc ions and protons, allowing cations to pass through. The molecular mechanism that ligands use to activate ZAC remains elusive. Here, we present three cryo-electron microscopy reconstru...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55807-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544482217000960 |
|---|---|
| author | Xuhang Lu Dongmei Li Yaojie Wang Gaohua Zhang Tianlei Wen Yue Lu Nan Jia Xuedi Wang Shenghai Chang Xing Zhang Jianping Lin Yu-hang Chen Xue Yang Yuequan Shen |
| author_facet | Xuhang Lu Dongmei Li Yaojie Wang Gaohua Zhang Tianlei Wen Yue Lu Nan Jia Xuedi Wang Shenghai Chang Xing Zhang Jianping Lin Yu-hang Chen Xue Yang Yuequan Shen |
| author_sort | Xuhang Lu |
| collection | DOAJ |
| description | Abstract The zinc-activated channel (ZAC) is an atypical mammalian cys-loop receptor (CLR) that is activated by zinc ions and protons, allowing cations to pass through. The molecular mechanism that ligands use to activate ZAC remains elusive. Here, we present three cryo-electron microscopy reconstructions of human ZAC (hZAC) under different conditions. These three hZAC structures display highly similar conformations to one another, forming symmetrical homo-pentamers with a central ion-conduction pore. The hZAC protomer comprises an extracellular domain (ECD) and a transmembrane domain (TMD), sharing more structural similarity with anion-permeable CLRs, such as glycine receptors and type A γ-aminobutyric acid receptors. Notably, hZAC possesses a distinctive C-tail that establishes a disulfide bond with the loop M2-M3 in the TMD and occupies what is typically the canonical neurotransmitter orthosteric site in other mammalian CLRs. Moreover, the tip of the cys-loop creates an unprecedented orthosteric site in hZAC. The binding of Zn2+ triggers a conformational shift in the cys-loop, which presumably prompts the loop M2-M3 to move and open the channel gate. This study sheds light on the assembly of the channel, its structural features, and the process of signal transduction in hZAC. |
| format | Article |
| id | doaj-art-f9230a11f2304c78918c83c5b568f45c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f9230a11f2304c78918c83c5b568f45c2025-01-12T12:31:35ZengNature PortfolioNature Communications2041-17232025-01-0116111210.1038/s41467-024-55807-5Structural insights into the activation mechanism of the human zinc-activated channelXuhang Lu0Dongmei Li1Yaojie Wang2Gaohua Zhang3Tianlei Wen4Yue Lu5Nan Jia6Xuedi Wang7Shenghai Chang8Xing Zhang9Jianping Lin10Yu-hang Chen11Xue Yang12Yuequan Shen13State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityCollege of Pharmacy, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, The Innovative Academy of Seed Design, Chinese Academy of SciencesState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityDepartment of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityDepartment of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang UniversityCollege of Pharmacy, Nankai UniversityState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, The Innovative Academy of Seed Design, Chinese Academy of SciencesState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai UniversityAbstract The zinc-activated channel (ZAC) is an atypical mammalian cys-loop receptor (CLR) that is activated by zinc ions and protons, allowing cations to pass through. The molecular mechanism that ligands use to activate ZAC remains elusive. Here, we present three cryo-electron microscopy reconstructions of human ZAC (hZAC) under different conditions. These three hZAC structures display highly similar conformations to one another, forming symmetrical homo-pentamers with a central ion-conduction pore. The hZAC protomer comprises an extracellular domain (ECD) and a transmembrane domain (TMD), sharing more structural similarity with anion-permeable CLRs, such as glycine receptors and type A γ-aminobutyric acid receptors. Notably, hZAC possesses a distinctive C-tail that establishes a disulfide bond with the loop M2-M3 in the TMD and occupies what is typically the canonical neurotransmitter orthosteric site in other mammalian CLRs. Moreover, the tip of the cys-loop creates an unprecedented orthosteric site in hZAC. The binding of Zn2+ triggers a conformational shift in the cys-loop, which presumably prompts the loop M2-M3 to move and open the channel gate. This study sheds light on the assembly of the channel, its structural features, and the process of signal transduction in hZAC.https://doi.org/10.1038/s41467-024-55807-5 |
| spellingShingle | Xuhang Lu Dongmei Li Yaojie Wang Gaohua Zhang Tianlei Wen Yue Lu Nan Jia Xuedi Wang Shenghai Chang Xing Zhang Jianping Lin Yu-hang Chen Xue Yang Yuequan Shen Structural insights into the activation mechanism of the human zinc-activated channel Nature Communications |
| title | Structural insights into the activation mechanism of the human zinc-activated channel |
| title_full | Structural insights into the activation mechanism of the human zinc-activated channel |
| title_fullStr | Structural insights into the activation mechanism of the human zinc-activated channel |
| title_full_unstemmed | Structural insights into the activation mechanism of the human zinc-activated channel |
| title_short | Structural insights into the activation mechanism of the human zinc-activated channel |
| title_sort | structural insights into the activation mechanism of the human zinc activated channel |
| url | https://doi.org/10.1038/s41467-024-55807-5 |
| work_keys_str_mv | AT xuhanglu structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT dongmeili structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT yaojiewang structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT gaohuazhang structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT tianleiwen structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT yuelu structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT nanjia structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT xuediwang structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT shenghaichang structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT xingzhang structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT jianpinglin structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT yuhangchen structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT xueyang structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel AT yuequanshen structuralinsightsintotheactivationmechanismofthehumanzincactivatedchannel |