Transmembrane protein 94
P-type magnesium transporter activity
ERMA (TMEM94) is a P-type ATPase transporter for Mg&lt;sup&gt;2+&lt;/sup&gt; uptake in the endoplasmic reticulum.
Intracellular Mg<sup>2+</sup> (<sub>i</sub>Mg<sup>2+</sup>) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg<sup>2+</sup> transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major <sub>i</sub>Mg<sup>2+</sup> 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 <sub>ER</sub>Mg<sup>2+</sup> uptake. Experiments reveal that a tyrosine residue is crucial for Mg<sup>2+</sup> binding and activity in a mechanism conserved in both prokaryotic (mgtB and mgtA) and eukaryotic Mg<sup>2+</sup> ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca<sup>2+</sup> cycling in mouse Erma<sup>+/-</sup> cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of <sub>ER</sub>Mg<sup>2+</sup> uptake in eukaryotes.