ERMA (TMEM94) is a P-type ATPase Transporter for Mg Uptake in the Endoplasmic Reticulum

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 (mgtB and mgtA) and eukaryotic Mg ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca cycling in mouse Erma cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of Mg uptake in eukaryotes.