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

Neelanjan Vishnu1, Manigandan Venkatesan1, Travis R Madaris1

  • 1Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.

Molecular Cell
|March 21, 2024
PubMed

Insights

The endoplasmic reticulum (ER) is a key intracellular magnesium (Mg2+) storage site. A newly identified protein, ERMA (TMEM94), is crucial for transporting Mg2+ into the ER, impacting cardiac function.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Intracellular magnesium (iMg2+) is vital for cellular processes, yet its transport into organelles like the endoplasmic reticulum (ER) is poorly understood.
  • The ER serves as a significant reservoir for iMg2+.

Purpose of the Study:

  • To investigate the molecular mechanisms of Mg2+ transport into the ER.
  • To identify and characterize the protein responsible for refilling the ER Mg2+ compartment.

Main Methods:

  • Utilized conventional and AlphaFold2 protein structure prediction.
  • Conducted experimental analyses of ERMA protein function and Mg2+ binding.
  • Investigated ERMA's role in cardiac cells using mouse models and human induced pluripotent stem cell-derived cardiomyocytes.

Main Results:

  • Identified ERMA (TMEM94) as an ER-localized protein essential for Mg2+ uptake into the ER.
  • ERMA possesses a unique structure combining P-type ATPase and GMN domains for Mg2+ transport.
  • A specific tyrosine residue in ERMA is critical for Mg2+ binding and activity, a conserved mechanism across species.
  • ERMA deficiency leads to cardiac dysfunction, abnormal calcium cycling in cardiomyocytes, and is linked to human heart conditions.

Conclusions:

  • ERMA is a critical component of eukaryotic ER Mg2+ uptake.
  • ERMA's function is essential for maintaining cardiac health and proper Ca2+ handling.
Keywords:
AlphaFold2ERMAGMN motifP-type ATPaseRNAi screenTMEM94calciumendoplasmic reticulumhepatocyteshuman cardiomyocyteslactatemagnesiummitochondriamutationsrefilluptake

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