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Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus

Secretory pathway Ca(2+)/Mn(2+) ATPase 1 (SPCA1) actively transports cytosolic Ca(2+) and Mn(2+) into the Golgi lumen, playing a crucial role in cellular calcium and manganese homeostasis. Detrimental mutations of the ATP2C1 gene encoding SPCA1 cause Hailey-Hailey disease. Here, using nanobody/megab...

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Autores principales: Chen, Zhenghao, Watanabe, Satoshi, Hashida, Hironori, Inoue, Michio, Daigaku, Yasukazu, Kikkawa, Masahide, Inaba, Kenji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984183/
https://www.ncbi.nlm.nih.gov/pubmed/36867705
http://dx.doi.org/10.1126/sciadv.add9742
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author Chen, Zhenghao
Watanabe, Satoshi
Hashida, Hironori
Inoue, Michio
Daigaku, Yasukazu
Kikkawa, Masahide
Inaba, Kenji
author_facet Chen, Zhenghao
Watanabe, Satoshi
Hashida, Hironori
Inoue, Michio
Daigaku, Yasukazu
Kikkawa, Masahide
Inaba, Kenji
author_sort Chen, Zhenghao
collection PubMed
description Secretory pathway Ca(2+)/Mn(2+) ATPase 1 (SPCA1) actively transports cytosolic Ca(2+) and Mn(2+) into the Golgi lumen, playing a crucial role in cellular calcium and manganese homeostasis. Detrimental mutations of the ATP2C1 gene encoding SPCA1 cause Hailey-Hailey disease. Here, using nanobody/megabody technologies, we determined cryo–electron microscopy structures of human SPCA1a in the ATP and Ca(2+)/Mn(2+)-bound (E1-ATP) state and the metal-free phosphorylated (E2P) state at 3.1- to 3.3-Å resolutions. The structures revealed that Ca(2+) and Mn(2+) share the same metal ion–binding pocket with similar but notably different coordination geometries in the transmembrane domain, corresponding to the second Ca(2+)-binding site in sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). In the E1-ATP to E2P transition, SPCA1a undergoes similar domain rearrangements to those of SERCA. Meanwhile, SPCA1a shows larger conformational and positional flexibility of the second and sixth transmembrane helices, possibly explaining its wider metal ion specificity. These structural findings illuminate the unique mechanisms of SPCA1a-mediated Ca(2+)/Mn(2+) transport.
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spelling pubmed-99841832023-03-04 Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus Chen, Zhenghao Watanabe, Satoshi Hashida, Hironori Inoue, Michio Daigaku, Yasukazu Kikkawa, Masahide Inaba, Kenji Sci Adv Biomedicine and Life Sciences Secretory pathway Ca(2+)/Mn(2+) ATPase 1 (SPCA1) actively transports cytosolic Ca(2+) and Mn(2+) into the Golgi lumen, playing a crucial role in cellular calcium and manganese homeostasis. Detrimental mutations of the ATP2C1 gene encoding SPCA1 cause Hailey-Hailey disease. Here, using nanobody/megabody technologies, we determined cryo–electron microscopy structures of human SPCA1a in the ATP and Ca(2+)/Mn(2+)-bound (E1-ATP) state and the metal-free phosphorylated (E2P) state at 3.1- to 3.3-Å resolutions. The structures revealed that Ca(2+) and Mn(2+) share the same metal ion–binding pocket with similar but notably different coordination geometries in the transmembrane domain, corresponding to the second Ca(2+)-binding site in sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). In the E1-ATP to E2P transition, SPCA1a undergoes similar domain rearrangements to those of SERCA. Meanwhile, SPCA1a shows larger conformational and positional flexibility of the second and sixth transmembrane helices, possibly explaining its wider metal ion specificity. These structural findings illuminate the unique mechanisms of SPCA1a-mediated Ca(2+)/Mn(2+) transport. American Association for the Advancement of Science 2023-03-03 /pmc/articles/PMC9984183/ /pubmed/36867705 http://dx.doi.org/10.1126/sciadv.add9742 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Chen, Zhenghao
Watanabe, Satoshi
Hashida, Hironori
Inoue, Michio
Daigaku, Yasukazu
Kikkawa, Masahide
Inaba, Kenji
Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus
title Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus
title_full Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus
title_fullStr Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus
title_full_unstemmed Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus
title_short Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus
title_sort cryo-em structures of human spca1a reveal the mechanism of ca(2+)/mn(2+) transport into the golgi apparatus
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984183/
https://www.ncbi.nlm.nih.gov/pubmed/36867705
http://dx.doi.org/10.1126/sciadv.add9742
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