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Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2
Polyamines are important polycations that play critical roles in mammalian cells. ATP13A2 belongs to the orphan P5B adenosine triphosphatases (ATPase) family and has been established as a lysosomal polyamine exporter to maintain the normal function of lysosomes and mitochondria. Previous studies hav...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Singapore
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564547/ https://www.ncbi.nlm.nih.gov/pubmed/34728622 http://dx.doi.org/10.1038/s41421-021-00334-6 |
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author | Chen, Xudong Zhou, Mingze Zhang, Sensen Yin, Jian Zhang, Ping Xuan, Xujun Wang, Peiyi Liu, Zhiqiang Zhou, Boda Yang, Maojun |
author_facet | Chen, Xudong Zhou, Mingze Zhang, Sensen Yin, Jian Zhang, Ping Xuan, Xujun Wang, Peiyi Liu, Zhiqiang Zhou, Boda Yang, Maojun |
author_sort | Chen, Xudong |
collection | PubMed |
description | Polyamines are important polycations that play critical roles in mammalian cells. ATP13A2 belongs to the orphan P5B adenosine triphosphatases (ATPase) family and has been established as a lysosomal polyamine exporter to maintain the normal function of lysosomes and mitochondria. Previous studies have reported that several human neurodegenerative disorders are related to mutations in the ATP13A2 gene. However, the transport mechanism of ATP13A2 in the lysosome remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structures of three distinct intermediates of the human ATP13A2, revealing key insights into the spermine (SPM) transport cycle in the lysosome. The transmembrane domain serves as a substrate binding site and the C-terminal domain is essential for protein stability and may play a regulatory role. These findings advance our understanding of the polyamine transport mechanism, the lipid-associated regulation, and the disease-associated mutants of ATP13A2. |
format | Online Article Text |
id | pubmed-8564547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-85645472021-11-16 Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 Chen, Xudong Zhou, Mingze Zhang, Sensen Yin, Jian Zhang, Ping Xuan, Xujun Wang, Peiyi Liu, Zhiqiang Zhou, Boda Yang, Maojun Cell Discov Article Polyamines are important polycations that play critical roles in mammalian cells. ATP13A2 belongs to the orphan P5B adenosine triphosphatases (ATPase) family and has been established as a lysosomal polyamine exporter to maintain the normal function of lysosomes and mitochondria. Previous studies have reported that several human neurodegenerative disorders are related to mutations in the ATP13A2 gene. However, the transport mechanism of ATP13A2 in the lysosome remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structures of three distinct intermediates of the human ATP13A2, revealing key insights into the spermine (SPM) transport cycle in the lysosome. The transmembrane domain serves as a substrate binding site and the C-terminal domain is essential for protein stability and may play a regulatory role. These findings advance our understanding of the polyamine transport mechanism, the lipid-associated regulation, and the disease-associated mutants of ATP13A2. Springer Singapore 2021-11-02 /pmc/articles/PMC8564547/ /pubmed/34728622 http://dx.doi.org/10.1038/s41421-021-00334-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chen, Xudong Zhou, Mingze Zhang, Sensen Yin, Jian Zhang, Ping Xuan, Xujun Wang, Peiyi Liu, Zhiqiang Zhou, Boda Yang, Maojun Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 |
title | Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 |
title_full | Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 |
title_fullStr | Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 |
title_full_unstemmed | Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 |
title_short | Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2 |
title_sort | cryo-em structures and transport mechanism of human p5b type atpase atp13a2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564547/ https://www.ncbi.nlm.nih.gov/pubmed/34728622 http://dx.doi.org/10.1038/s41421-021-00334-6 |
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