7vpj

Cryo-EM structure of the human ATP13A2 (E1P-ADP state)

spinqualitylabelsall models 7vpj, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.5Å Ligands: ADP, ALF, MG, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The cytoplasmic polyamine maintains cellular homeostasis by chelating toxic metal cations, regulating transcriptional activity, and protecting DNA. ATP13A2 was identified as a lysosomal polyamine exporter responsible for polyamine release into the cytosol, and its dysfunction is associated with Alzheimer's disease and other neural degradation diseases. ATP13A2 belongs to the P5 subfamily of the P-type ATPase family, but its mechanisms remain unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human ATP13A2 under four different conditions, revealing the structural coupling between the polyamine binding and the dephosphorylation. Polyamine is bound at the luminal tunnel and recognized through numerous electrostatic and pi-cation interactions, explaining its broad specificity. The unique N-terminal domain is anchored to the lipid membrane to stabilize the E2P conformation, thereby accelerating the E1P-to-E2P transition. These findings reveal the distinct mechanism of P5B ATPases, thereby paving the way for neuroprotective therapy by activating ATP13A2. Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.,Tomita A, Daiho T, Kusakizako T, Yamashita K, Ogasawara S, Murata T, Nishizawa T, Nureki O Mol Cell. 2021 Dec 2;81(23):4799-4809.e5. doi: 10.1016/j.molcel.2021.11.001. Epub, 2021 Nov 18. PMID:34798056 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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