Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin

Plasma membrane Ca²⁺-ATPases (PMCAs) are key regulators of global Ca²⁺ homeostasis and local intracellular Ca²⁺ dynamics. Recently, Neuroplastin (NPTN) and basigin were identified as previously unrecognized obligatory subunits of PMCAs that dramatically increase the efficiency of PMCA-mediated Ca²⁺ clearance. Here, we report the cryo-EM structure of human PMCA1 (hPMCA1) in complex with NPTN at a resolution of 4.1 Å for the overall structure and 3.9 Å for the transmembrane domain. The single transmembrane helix of NPTN interacts with the TM_8-9-linker and TM10 of hPMCA1. The subunits are required for the hPMCA1 functional activity. The NPTN-bound hPMCA1 closely resembles the E1-Mg²⁺ structure of endo(sarco)plasmic reticulum Ca²⁺ ATPase and the Ca²⁺ site is exposed through a large open cytoplasmic pathway. This structure provides insight into how the subunits bind to the PMCAs and serves as an important basis for understanding the functional mechanisms of this essential calcium pump family.