ERMA (TMEM94) is a P-type ATPase transporter for Mg(2+) uptake in the endoplasmic reticulum.

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