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Conformational Cycle of Human Polyamine Transporter ATP13A2

Posted on: 2023-09-19 12:57

Polyamines are a class of compounds containing two or more amino groups, and in human cells, the precise regulation of polyamine homeostasis is essential to maintening cellular health. Polyamine homeostasis depends on two systems: the metabolic system, which regulates the production and degradation of polyamines, and the transport system, which determines the distribution of polyamines in the cell. The lysosomal transporter ATP13A2 exports polyamines from the lysosome to the cytoplasm and plays a critical role in balancing the concentration of polyamines between the cytoplasm and the lysosome. It had been discovered that abnormalities in the human ATP13A2 (hATP13A2) gene was associated with a number of diseases, including Kufor-Rakeb Syndrome (a rare autosomal recessive form of juvenile-onset atypical Parkinson disease) and Autosomal Recessive Spastic Paraplegia Type 78. Although ATP13A2 plays a key role in polyamine homeostasis, its molecular mechanism is still unclear. Recently, Professor Ruhong Zhou from College of Life Sciences, Zhejiang University and Shanghai Institute of Advanced Study, Zhejiang University and collaborators jointly published a study titled Conformational cycle of human polyamine transporter ATP13A2 in Nature Communications. The authors captured high-resolution atomic structures of almost the entire conformational cycle of the hATP13A2 polyamine transporter by cryo-electron microscopy (Figure 1), and performed molecular dynamics simulations and mass spectrometry to reveal the molecular mechanism of polyamine transport to reveal structural basis for the recruitment, transport, and release of human ATP13A2 polyamine substrates. The work expanded out understanding in pathogenic mechanism of hATP13A2 in neuronal diseases and would facilitate drug design.
1. Polyamine recruitment. The first step in transporting substrates from the luminal side to the cytoplasmic side is the recruitment of polyamines to the hATP13A2 protein. The team identified a narrow binding pocket on the luminal side of the endo/lysosome with an outward-opening structure in the cryo-electron microscopy E2P structure of hATP13A2. Molecular dynamics simulations demonstrated that this is the entry site for polyamine recruitment.
2. Polyamine transport. With the energy release of dephosphorylation hydrolysis, phosphorylated hATP13A2 switches from the E2P state to the E2-Pi state, driving the movement of substrates from the cytosolic side to the other side. Although the cryo-electron microscopy structure did not capture the exact binding site of the polyamine here, the team confirmed the second substrate binding site of the polyamine is on the intracellular sidevia through coarse-grained molecular dynamics simulations, mutation function experiments, and cross-linked mass spectrometry. This is the first capture of the intermediate state in the polyamine transport.
3. Polyamine release. Accompanied by the release of phosphate ions, hATP13A2 enters the E2 state prior to substrate release. The team observed a large number of more dynamic lipid analogs around substrate release pocket in the cryo electron density map. The authors then examined the interaction of lipids and polyamines through coarse-grained molecular dynamics simulations (Figure 2) and found that these lipids were most likely strongly negatively-charged phospholipids, e.g., phosphatidylinositol 4,5-bisphosphate (PIP2). Finally, using molecular dynamics simulations that accounted for all atoms, the authors identified a third, highly hydrated polyamine-binding site, revealing the complete polyamine transport pathway.

In summary, the work resolved and modeled a series of conformational states of the full conformational cycle of the human polyamine transporter protein ATP13A2 via structural and computational biology methods and revealed the transport mechanism of the substrate polyamine molecule (Figure 3), providing guidance for subsequent structure-based drug design.
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