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Conformational cycle of human polyamine transporter ATP13A2.
- Source :
- Nature Communications; 4/8/2023, Vol. 14 Issue 1, p1-12, 12p
- Publication Year :
- 2023
-
Abstract
- Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases. ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson's disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 14
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 162970195
- Full Text :
- https://doi.org/10.1038/s41467-023-37741-0