Intracellular Mg (Mg) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major Mg compartment refilled by a largely uncharacterized ER-localized protein, TMEM94. Conventional and AlphaFold2 predictions suggest that ERMA (TMEM94) is a multi-pass transmembrane protein with large cytosolic headpiece actuator, nucleotide, and phosphorylation domains, analogous to P-type ATPases. However, ERMA uniquely combines a P-type ATPase domain and a GMN motif for Mg uptake. Experiments reveal that a tyrosine residue is crucial for Mg binding and activity in a mechanism conserved in both prokaryotic ( and ) and eukaryotic Mg ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca cycling in mouse cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of Mg uptake in eukaryotes.

中文翻译：

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ERMA (TMEM94) 是一种 P 型 ATP 酶转运蛋白，用于内质网中 Mg2+ 的摄取

细胞内镁 (Mg) 与真核生物中的磷酸代谢物、核酸和蛋白质结合。人们对细胞内的区室化和镁离子转运入/出细胞器（例如内质网（ER））的分子细节知之甚少。我们发现 ER 是一个主要的镁室，由一种很大程度上未表征的 ER 定位蛋白 TMEM94 重新填充。传统和 AlphaFold2 预测表明 ERMA (TMEM94) 是一种多次跨膜蛋白，具有大型胞质头件致动器、核苷酸和磷酸化结构域，类似于 P 型 ATP 酶。然而，ERMA 独特地将 P 型 ATP 酶结构域和用于镁吸收的 GMN 基序结合在一起。实验表明，酪氨酸残基对于原核 ( 和 ) 和真核 Mg ATP 酶中保守的机制中的 Mg 结合和活性至关重要。单倍体不足导致的心脏功能障碍、小鼠心肌细胞中的异常 Ca 循环以及人 iPSC 心肌细胞中的 ERMA mRNA 沉默共同将 ERMA 定义为真核生物中镁吸收的重要组成部分。