Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD, 20892, USA.
Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD, 20892, USA; Department of Anatomy, Physiology, and Genetics, Uniformed Services University, Bethesda, MD, USA.
Cell Calcium. 2022 Sep;106:102631. doi: 10.1016/j.ceca.2022.102631. Epub 2022 Jul 11.
The ER-resident proteins STIM1 together with the plasma membrane (PM)-localized Orai1 channels constitute the molecular components of the store-operated Ca entry (SOCE) pathway. Prepositioning of STIM1 to the peripheral ER close to the PM ensures its efficient interaction with Orai1 upon a decrease in the ER luminal Ca concentration. The C-terminal polybasic domain of STIM1 has been identified as mediating the interaction with PM phosphoinositides and hence positions the molecule to ER-PM contact sites. Here we show that STIM1 requires PM phosphatidylinositol 4-phosphate (PI4P) for efficient PM interaction. Accordingly, oxysterol binding protein related proteins (ORPs) that work at ER-PM junctions and consume PI4P gradients exert important control over the Ca entry process. These studies reveal an important connection between non-vesicular lipid transport at ER-PM contact sites and regulation of ER Castore refilling.
内质网驻留蛋白 STIM1 与位于质膜 (PM) 上的 Orai1 通道一起构成了钙库操纵性钙内流 (SOCE) 途径的分子组成部分。STIM1 预定位在内质网的外周靠近质膜，确保其在内质网腔钙浓度降低时与 Orai1 有效相互作用。STIM1 的 C 端多碱性结构域被确定为介导与 PM 磷酸肌醇的相互作用，从而将分子定位到 ER-PM 接触位点。在这里，我们表明 STIM1 需要 PM 磷脂酰肌醇 4-磷酸 (PI4P) 才能有效地与 PM 相互作用。因此，在 ER-PM 连接点处起作用并消耗 PI4P 梯度的氧化固醇结合蛋白相关蛋白 (ORPs) 对钙内流过程发挥重要的控制作用。这些研究揭示了 ER-PM 接触位点处非囊泡脂质转运与内质网钙再填充调节之间的重要联系。
