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.