Structural basis of polyamine transport by human ATP13A2 (PARK9)

• Published in: Molecular cell Vol. 81; no. 22; pp. 4635 - 4649.e8
• Main Authors: Sim, Sue Im, von Bülow, Sören, Hummer, Gerhard, Park, Eunyong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.11.2021
• Subjects: Animals; Biological Transport; Catalysis; cryo-EM; Cryoelectron Microscopy; Cytosol - metabolism; Humans; Lipids - chemistry; lysosome; Lysosomes - chemistry; membrane protein; Molecular Dynamics Simulation; P-type ATPase; P5B-ATPase; Parkinson Disease - metabolism; Parkinson's disease; Phosphorylation; polyamine; Polyamines - chemistry; Protein Conformation; Protein Domains; Proton-Translocating ATPases - chemistry; Saccharomyces cerevisiae - metabolism; spermine; Spodoptera; transporter; polyamine; P5B-ATPase; Parkinson's disease; transporter; spermine; membrane protein; P-type ATPase; lysosome; cryo-EM
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.08.017

Polyamines are small, organic polycations that are ubiquitous and essential to all forms of life. Currently, how polyamines are transported across membranes is not understood. Recent studies have suggested that ATP13A2 and its close homologs, collectively known as P5B-ATPases, are polyamine transporters at endo-/lysosomes. Loss-of-function mutations of ATP13A2 in humans cause hereditary early-onset Parkinson's disease. To understand the polyamine transport mechanism of ATP13A2, we determined high-resolution cryoelectron microscopy (cryo-EM) structures of human ATP13A2 in five distinct conformational intermediates, which together, represent a near-complete transport cycle of ATP13A2. The structural basis of the polyamine specificity was revealed by an endogenous polyamine molecule bound to a narrow, elongated cavity within the transmembrane domain. The structures show an atypical transport path for a water-soluble substrate, in which polyamines may exit within the cytosolic leaflet of the membrane. Our study provides important mechanistic insights into polyamine transport and a framework to understand the functions and mechanisms of P5B-ATPases. [Display omitted] •High-resolution cryo-EM structures of human ATP13A2 in five distinct conformations•Unique features of ATP13A2 in comparison to other P-type ATPases•Structural basis of polyamine substrate binding to the membrane domain of ATP13A2•Conformational changes along the transport cycle and a model for polyamine transport The P-type ATPase ATP13A2 is an endo-/lysosomal polyamine transporter, defects of which are implicated in hereditary forms of Parkinson disease. Sim et al. report structures of human ATP13A2 in five distinct conformations, representing a near-complete catalytic cycle. This work reveals the mechanistic basis of polyamine recognition and transport by ATP13A2.