Structural mechanisms of PIP₂ activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.

ABSTRACT: Na⁺/Ca²⁺ exchangers (NCXs) transport Ca²⁺ across the plasma membrane in exchange for Na⁺ and play a vital role in maintaining cellular Ca²⁺ homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na⁺-dependent inactivation and Ca²⁺ activation of NCX1. Here we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP₂), or pharmacological inhibitor SEA0400 that enhances the inactivation of the exchanger. We demonstrate that PIP₂ binding

SUBMITTER: Xue J 

PROVIDER: S-EPMC11643123 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature