ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum

Intracellular Mg2+ (iMg2+) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg2+ transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major iMg2+ 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 ERMg2+ uptake. Experiments reveal that a tyrosine residue is crucial for Mg2+ binding and activity in a mechanism conserved in both prokaryotic (mgtB and mgtA) and eukaryotic Mg2+ ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca2+ cycling in mouse Erma+/− cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of ERMg2+ uptake in eukaryotes. [Display omitted] •ERMA (TMEM94) is a eukaryotic P-type ATPase essential for Mg2+ uptake into the ER•ERMA is an integral membrane protein with P-type ATPase catalytic headpiece domain•ERMA combines an Mg2+-binding GMN motif and a conserved Tyrosine residue for Mg2+ uptake•ERMA haploinsufficient mice are predisposed to cardiac diastolic dysfunction Eukaryotic cellular Mg2+ dynamics have been an open question in the field for several decades. Here, authors unveil ERMA as a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum. Identification of this core molecular factor in Mg2+ dynamics will aid in understanding the intracellular Mg2+ ion homeostasis and physiological effects.