細胞内の高速ポンプの働きを解明(High-speed pumps in the cell)

2025-09-17 マックス・プランク研究所

Cryo-EM structure of PMCA bound to neuroplastin (NPTN). The N-domain, A-domain, P-domain and M-domain of PMCA2 are red, yellow, blue and brown, respectively. NPTN is shown in grey. Densities corresponding to lipids and glycans are colored purple and green, respectively.

<関連情報>

• https://www.mpg.de/25421033/high-speed-pumps-in-the-cell
• https://www.nature.com/articles/s41586-025-09402-3

細胞膜Ca2+-ATPaseによる超高速輸送の分子機構 Molecular mechanism of ultrafast transport by plasma membrane Ca2+-ATPases

Deivanayagabarathy Vinayagam,Oleg Sitsel,Uwe Schulte,Cristina E. Constantin,Wout Oosterheert,Daniel Prumbaum,Gerd Zolles,Bernd Fakler & Stefan Raunser
Nature  Published:20 August 2025
DOI:https://doi.org/10.1038/s41586-025-09402-3

Abstract

Tight control of intracellular Ca²⁺ levels is fundamental as they are used to control numerous signal transduction pathways¹. Plasma membrane Ca²⁺-ATPases (PMCAs) have a crucial role in this process by extruding Ca²⁺ against a steep concentration gradient from the cytosol to the extracellular space². Although new details of PMCA biology are constantly being uncovered, the structural basis of the most distinguishing features of these pumps, namely, transport rates in the kilohertz range and regulation of activity by the plasma membrane phospholipid PtdIns(4,5)P₂, has so far remained elusive. Here we present the structures of mouse PMCA2 in the presence and absence of its accessory subunit neuroplastin in eight different stages of its transport cycle. Combined with whole-cell recordings that accurately track PMCA-mediated Ca²⁺ extrusion in intact cells, these structures enable us to establish the first comprehensive transport model for a PMCA, reveal the role of disease-causing mutations and uncover the structural underpinnings of regulatory PMCA–phospholipid interaction. The transport cycle-dependent dynamics of PtdIns(4,5)P₂ are fundamental for its role as a ‘latch’ promoting the fast release of Ca²⁺ and opening a passageway for counter-ions. These actions are required for maintaining the ultra-fast transport cycle. Moreover, we identify the PtdIns(4,5)P₂-binding site as an unanticipated target for drug-mediated manipulation of intracellular Ca²⁺ levels. Our work provides detailed structural insights into the uniquely fast operation of native PMCA-type Ca²⁺ pumps and its control by membrane lipids and drugs.