Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Physiology

Background:

• Magnesium ions (Mg²⁺) are crucial for mitochondrial functions including ATP synthesis and metabolism.
• The MRS2 channel in the inner mitochondrial membrane regulates Mg²⁺ influx and homeostasis.
• MRS2 dysfunction impairs mitochondrial metabolism, but its transport mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms of Mg²⁺ translocation and regulation by the human MRS2 channel.
• To determine the structural basis of MRS2 function using high-resolution cryo-electron microscopy.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine human MRS2 structures in the presence and absence of Mg²⁺.
• Site-directed mutagenesis to identify key gating residues.
• Cellular divalent ion uptake assays to validate functional roles.

Main Results:

• Determined homo-pentameric structures of human MRS2 at 2.8 Å and 3.3 Å resolution.
• Identified R332 and M336 as critical gating residues for Mg²⁺ translocation.
• Discovered two novel Mg²⁺-binding sites in the MRS2 soluble domain, distinct from prokaryotic CorA.

Conclusions:

• Provides a molecular understanding of Mg²⁺ transport and regulation by the human MRS2 channel.
• Highlights the role of specific residues and binding sites in MRS2 gating and function.
• Offers insights into maintaining mitochondrial Mg²⁺ homeostasis.