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

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. StathopulosMuniswamy Madesh

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1321-1337.e11
JournalMolecular Cell
Volume84
Issue number7
DOIs
StatePublished - Apr 4 2024

Keywords

  • AlphaFold2
  • ERMA
  • GMN motif
  • P-type ATPase
  • RNAi screen
  • TMEM94
  • calcium
  • endoplasmic reticulum
  • hepatocytes
  • human cardiomyocytes
  • lactate
  • magnesium
  • mitochondria
  • mutations
  • refill
  • uptake

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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