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. Copyright © 2024 Elsevier Inc. All rights reserved.

Citation

Neelanjan Vishnu, Manigandan Venkatesan, Travis R Madaris, Mridula K Venkateswaran, Kristen Stanley, Karthik Ramachandran, Adhishree Chidambaram, Abitha K Madesh, Wenli Yang, Jyotsna Nair, Melanie Narkunan, Tharani Muthukumar, Varsha Karanam, Leroy C Joseph, Amy Le, Ayodeji Osidele, M Imran Aslam, John P Morrow, May C Malicdan, Peter B Stathopulos, Muniswamy Madesh. ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum. Molecular cell. 2024 Apr 04;84(7):1321-1337.e11

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PMID: 38513662

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