Palmitoylation is the post-translational, covalent and reversible conjugation of a 16C saturated fatty acid to cysteine residues of proteins. The sodium calcium exchanger NCX1 is palmitoylated at a single cysteine residue in its large regulatory intracellular loop. Inactivation, mediated by the NCX1 inhibitory region XIP, is drastically impaired in unpalmitoylatable NCX1. The ability of XIP to bind and inactivate NCX1 is largely determined by NCX1 palmitoylation, which induces local conformational changes in the NCX1 intracellular loop to enable XIP to engage its binding site. Consequently, NCX1 palmitoylation regulates intracellular calcium by changing NCX1 sensitivity to inactivation. NCX1 palmitoylation is a dynamic phenomenon which is catalyzed by the palmitoyl acyl transferase zDHHC5 and reversed by the thioesterase APT1, with the switch between palmitoylated and depalmitoylated states, which has profound effects on NCX1 lipid interactions, influenced by NCX1 conformational poise. Herein we review the molecular and cellular consequences of NCX1 palmitoylation and its physiological relevance and highlight the importance of palmitoylation for NCX1 activity. We discuss the cellular control of protein palmitoylation and depalmitoylation, the relationship between lipid microdomains and lipidated and phospholipid binding proteins, and highlight the important unanswered questions in this emerging field.

棕榈酰化是 16C 饱和脂肪酸与蛋白质的半胱氨酸残基的翻译后、共价和可逆缀合。钠钙交换器 NCX1 在其大型调节细胞内环中的单个半胱氨酸残基处被棕榈酰化。由 NCX1 抑制区 XIP 介导的失活在不可棕榈酰化的 NCX1 中严重受损。XIP 结合和灭活 NCX1 的能力很大程度上取决于 NCX1 棕榈酰化，这会诱导 NCX1 细胞内环的局部构象变化，使 XIP 能够结合其结合位点。因此，NCX1 棕榈酰化通过改变 NCX1 对失活的敏感性来调节细胞内钙。NCX1 棕榈酰化是一种动态现象，由棕榈酰酰基转移酶 zDHHC5 催化并由硫酯酶 APT1 逆转，随着棕榈酰化和去棕榈酰化状态之间的转换，这对 NCX1 脂质相互作用具有深远的影响，受 NCX1 构象平衡的影响。在此，我们回顾了 NCX1 棕榈酰化的分子和细胞后果及其生理相关性，并强调了棕榈酰化对 NCX1 活性的重要性。我们讨论了蛋白质棕榈酰化和脱棕榈酰化的细胞控制、脂质微区与脂化和磷脂结合蛋白之间的关系，并强调了这一新兴领域中尚未解决的重要问题。在此，我们回顾了 NCX1 棕榈酰化的分子和细胞后果及其生理相关性，并强调了棕榈酰化对 NCX1 活性的重要性。我们讨论了蛋白质棕榈酰化和脱棕榈酰化的细胞控制、脂质微区与脂化和磷脂结合蛋白之间的关系，并强调了这一新兴领域中尚未解决的重要问题。在此，我们回顾了 NCX1 棕榈酰化的分子和细胞后果及其生理相关性，并强调了棕榈酰化对 NCX1 活性的重要性。我们讨论了蛋白质棕榈酰化和脱棕榈酰化的细胞控制、脂质微区与脂化和磷脂结合蛋白之间的关系，并强调了这一新兴领域中尚未解决的重要问题。